U.S. patent application number 09/794180 was filed with the patent office on 2001-10-18 for triazole antifungal agent.
This patent application is currently assigned to SANKYO COMPANY LIMITED. Invention is credited to Konosu, Toshiyuki, Miyaoka, Takeo, Oida, Sadao, Somada, Atsushi, Tajima, Yawara, Tanaka, Teruo, Yasuda, Hiroshi.
Application Number | 20010031778 09/794180 |
Document ID | / |
Family ID | 13735652 |
Filed Date | 2001-10-18 |
United States Patent
Application |
20010031778 |
Kind Code |
A1 |
Oida, Sadao ; et
al. |
October 18, 2001 |
Triazole antifungal agent
Abstract
A compound having the formula: 1 [wherein Ar.sup.1 represents a
phenyl which may be substituted, Ar.sup.2 represents a phenyl which
may be substituted or a heterocyclic group which may be
substituted, R.sup.0 represents a hydrogen atom or a lower alkyl;
R.sup.1 represents a lower alkyl; R.sup.2 to R.sup.5 represent a
hydrogen atom or an alkyl which may be substituted with halogen, n
represents 0 to 2; p represents 0 or 1; q, r and s represent 0 to
2; A represents a 4- to 7-membered carbon ring or a 4- to
7-membered heterocyclic group]. The compound of the present
invention exhibits excellent antifugal activities.
Inventors: |
Oida, Sadao; (Yokohama-shi,
JP) ; Tanaka, Teruo; (Yokohama-shi, JP) ;
Tajima, Yawara; (Kuki-shi, JP) ; Konosu,
Toshiyuki; (Kawasaki-shi, JP) ; Somada, Atsushi;
(Ohmiya-shi, JP) ; Miyaoka, Takeo; (Funabashi-shi,
JP) ; Yasuda, Hiroshi; (Yokohama-shi, JP) |
Correspondence
Address: |
FRISHAUF, HOLTZ, GOODMAN, LANGER & CHICK, P.C.
767 Third Avenue - 25th Floor
New York
NY
10017-2023
US
|
Assignee: |
SANKYO COMPANY LIMITED
5-1, Nihonbashi Honcho 3-chome, Chuo-ku
Tokyo
JP
|
Family ID: |
13735652 |
Appl. No.: |
09/794180 |
Filed: |
February 27, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09794180 |
Feb 27, 2001 |
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09241369 |
Feb 1, 1999 |
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09241369 |
Feb 1, 1999 |
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08944304 |
Oct 6, 1997 |
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5977152 |
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08944304 |
Oct 6, 1997 |
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PCT/JP96/00932 |
Apr 5, 1996 |
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Current U.S.
Class: |
514/383 ;
548/268.2 |
Current CPC
Class: |
C07D 231/12 20130101;
A01N 43/653 20130101; C07D 249/08 20130101; A61P 31/10 20180101;
C07D 233/56 20130101 |
Class at
Publication: |
514/383 ;
548/268.2 |
International
Class: |
A61K 031/4196; C07D
249/08 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 6, 1995 |
JP |
HEI 7-81052 |
Claims
1. A compound having the formula: 300wherein Ar.sup.1 represents a
phenyl group or a phenyl group having 1 to 3 substituent(s) (said
substituent(s) represent(s) a halogen atom or a trifluoromethyl
group); Ar.sup.2 represents phenyl, a 5- or 6-membered aromatic
heterocyclic group (said aromatic heterocyclic group has at least
one nitrogen, oxygen or sulfur atom) or a phenyl group or a 5- to
6-membered aromatic heterocyclic group having 1 to 3 substituent(s)
(said substituent(s) represent(s) a lower alkyl group, a lower
alkoxy group, a halogen atom, a lower alkyl group substituted with
a halogen atom or halogen atoms, a lower alkoxy group substituted
with a halogen atom or halogen atoms, a nitro group, a cyano group,
a --S(O).sub.mR.sup.6 group (R.sup.6 represents a lower alkyl group
which may be substituted with a halogen atom or halogen atoms and m
represents 0, 1 or 2) or a --NECOR.sup.7 group (R.sup.7 represents
a lower alkyl group) and said aromatic heterocyclic group has at
least one nitrogen, oxygen or sulfur atom); R.sup.0 represents a
hydrogen atom or a lower alkyl group; R.sup.1 represents a lower
alkyl group; R.sup.2, R.sup.3, R.sup.4 and R.sup.5 may be the same
or different and represent a hydrogen atom, a lower alkyl group or
a lower alkyl group substituted with a halogen atom or halogen
atoms and, where q and/or s represent 2, each of R.sup.2, R.sup.3,
R.sup.4 and R.sup.5 represents independently a group which is the
same or different from the other R.sup.2, R.sup.3, R.sup.4 and
R.sup.5 respectively; n represents 0, 1 or 2; p represents 0 or 1;
q, r and s represent 0, 1 or 2; and A represents a 4- to 7-membered
aliphatic carbocyclic group comprising 4 to 7 carbon atoms or a 4-
to 7-membered aliphatic heterocyclic group having at least one
nitrogen, oxygen or sulfur atom, or a pharmacologically acceptable
salt thereof.
2. A triazole compound or a pharmacologically acceptable salt
thereof according to claim 1, wherein Ar.sup.1 is a phenyl group
having 1 to 3 substituent(s) (said substituent(s) represent(s) a
halogen atom or a trifluoromethyl group).
3. A triazole compound or a pharmacologically acceptable salt
thereof according to claim 1, wherein Ar.sup.1 is a phenyl group
having 1 or 2 substituent(s) (said substituent(s) represent(s) a
fluorine atom, a chlorine atom or a trifluoromethyl group).
4. A triazole compound or a pharmacologically acceptable salt
thereof according to claims 1 to 3, wherein Ar.sup.2 represents a
phenyl group, a 5- or 6-membered aromatic heterocyclic group (said
aromatic heterocyclic group has at least one nitrogen, oxygen or
sulfur atom) or a phenyl group or a 5- or 6-membered aromatic
heterocyclic group having 1 to 3 substituent(s) (said
substituent(s) represent(s) a lower alkyl group, a halogen atom, a
lower alkyl group substituted with a halogen atom or halogen atoms,
a lower alkoxy group substituted with a halogen atom or halogen
atoms, a nitro group, a cyano group or a --S(O).sub.mR.sup.6 group
(R.sup.6 represents a lower alkyl group which may be substituted
with a halogen atom or halogen atoms and m represents 0, 1 or 2)
and said aromatic heterocyclic group has at least one nitrogen,
oxygen or sulfur atom).
5. A triazole compound or a pharmacologically acceptable salt
thereof according to claims 1 to 3, wherein Ar.sup.2 represents a
phenyl group, a 5- or 6-membered aromatic heterocyclic group (said
aromatic heterocyclic group has one nitrogen, oxygen or sulfur
atom) or a phenyl group or a 5- to 6-membered aromatic heterocyclic
group having 1 to 3 substituent(s) (said substituent(s)
represent(s) a lower alkyl group, a halogen atom, a lower alkyl
group substituted with a halogen atom or halogen atoms, a lower
alkoxy group substituted with a halogen atom or halogen atoms, a
nitro group, a cyano group or a --S(O).sub.mR.sup.6 group (R.sup.6
represents a lower alkyl group which may be substituted with a
halogen atom or halogen atoms and m represents 0, 1 or 2) and said
aromatic heterocyclic group has one nitrogen, oxygen or sulfur
atom).
6. A triazole compound or a pharmacologically acceptable salt
thereof according to claims 1 to 3, wherein Ar.sup.2 represents a
phenyl group, a 5- or 6-membered aromatic heterocyclic group (said
aromatic heterocyclic group has one nitrogen or sulfur atom) or a
phenyl group or a 5- or 6-membered aromatic heterocyclic group
having 1 or 2 substituent(s) (said substituent(s) represent(s) a
lower alkyl group, a halogen atom, a lower alkyl group substituted
with a halogen atom or halogen atoms, a lower alkoxy group
substituted with a halogen atom or halogen atoms, a nitro group, a
cyano group or a --S(O).sub.mR.sup.6 group (R.sup.6 represents a
lower alkyl group which may be substituted with a halogen atom or
halogen atoms and m represents 0, 1 or 2) and said aromatic
heterocyclic group has one nitrogen or sulfur atom).
7. A triazole compound or a pharmacologically acceptable salt
thereof according to claims 1 to 3, wherein Ar.sup.2 represents a
phenyl group or a pyridyl group or a phenyl group, a pyridyl group
or a thienyl group having 1 or 2 substituent(s) (said
substituent(s) represent(s) a lower alkyl group, a halogen atom, a
lower alkyl group substituted with a halogen atom or halogen atoms,
a lower alkoxy group substituted with a halogen atom or halogen
atoms, a nitro group, a cyano group or a --S(O).sub.mR.sup.6 group
(R.sup.6 represents a lower alkyl group which may be substituted
with a halogen atom or halogen atoms and m represents 0, 1 or
2).
8. A triazole compound or a pharmacologically acceptable salt
thereof according to claims 1 to 7, wherein R.sup.0 is a hydrogen
atom, a methyl group, an ethyl group or a propyl group.
9. A triazole compound or a pharmacologically acceptable salt
thereof according to claims 1 to 7, wherein R.sup.0 is a hydrogen
atom, a methyl group or an ethyl group.
10. A triazole compound or a pharmacologically acceptable salt
thereof according to claims 1 to 7, wherein R.sup.0 is a hydrogen
atom or a methyl group.
11. A triazole compound or a pharmacologically acceptable salt
thereof according to claims 1 to 10, wherein R.sup.1 is a methyl
group, an ethyl group or a propyl group.
12. A triazole compound or a pharmacologically acceptable salt
thereof according to claims 1 to 10, wherein R.sup.1 is a methyl
group or an ethyl group.
13. A triazole compound or a pharmacologically acceptable salt
thereof according to claims 1 to 10, wherein R.sup.1 is a methyl
group.
14. A triazole compound or a pharmacologically acceptable salt
thereof according to claims 1 to 13, wherein R.sup.2, R.sup.3,
R.sup.4 and R.sup.5 may be the same or different and are a hydrogen
atom, a lower alkyl group or a lower alkyl group substituted with a
fluorine or chlorine atom or atoms.
15. A triazole compound or a pharmacologically acceptable salt
thereof according to claims 1 to 13, wherein R.sup.2, R.sup.3,
R.sup.4 and R.sup.5 may be the same or different and are a hydrogen
atom, a methyl group, an ethyl group or a propyl group or a methyl
group, an ethyl group or a propyl group substituted with a fluorine
or chlorine atom or atoms.
16. A triazole compound or a pharmacologically acceptable salt
thereof according to claims 1 to 13, wherein R.sup.2, R.sup.3,
R.sup.4 and R.sup.5 may be the same or different and are a hydrogen
atom, a methyl group or an ethyl group or a methyl group or an
ethyl group substituted with a fluorine or chlorine atom or
atoms.
17. A triazole compound or a pharmacologically acceptable salt
thereof according to claims 1 to 13, wherein R.sup.2, R.sup.3,
R.sup.4 and R.sup.5 may be the same or different and are a hydrogen
atom or a methyl group or a methyl group substituted with a
fluorine or chlorine atom or atoms.
18. A triazole compound or a pharmacologically acceptable salt
thereof according to claims 2 to 17, wherein n is 0, 1 or 2.
19. A triazole compound or a pharmacologically acceptable salt
thereof according to claims 1 to 17, wherein n is 0.
20. A triazole compound or a pharmacologically acceptable salt
thereof according to claims 2 to 19, wherein p is 0 or 1.
21. A triazole compound or a pharmacologically acceptable salt
thereof according to claims 2 to 20, wherein q, r and s are 0, 1 or
2.
22. A triazole compound or a pharmacologically acceptable salt
thereof according to claims 1 to 21, wherein A is a 5- or
6-membered aliphatic carbocyclic group comprising 5 or 6 carbon
atoms or a 4- to 6-membered aliphatic heterocyclic group having at
least one nitrogen, oxygen or sulfur atom.
23. A triazole compound or a pharmacologically acceptable salt
thereof according to claims 1 to 21, wherein A is a 5- or
6-membered aliphatic carbocyclic group comprising 5 or 6 carbon
atoms or a 4- to 6-membered aliphatic heterocyclic group having 1
or 2 nitrogen, oxygen or sulfur atom(s).
24. A triazole compound or a pharmacologically acceptable salt
thereof according to claims 1 to 21, wherein A is cyclohexane,
piperidine, 1,3-dioxane or 1,3-dithiane ring.
25.
2-(2,4-Difluorophenyl)-3-[[2-[2-[4-(trifluoromethyl)phenyl]vinyl]-1,3--
dioxan-5-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol,
2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[2-[2-[4-(trifluorome-
thoxy)phenyl]vinyl]-1,3-dioxan-5-yl]thio]-2-butanol,
2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[2-[4-[4-(trifluorome-
thyl)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-2-butanol,
2-(2,4-difluorophenyl)-3-[[2-[4-[4-(2,2,3,3-tetrafluoropropoxy)
phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-1-(1-1,2,4-triazol-1-yl)-
-2-butanol, 2-(2,4-difluorophenyl)-3-[[2-[4-[4-(chlorophenyl)
-4,4,4-trifluoro-1,3-pentadien-1-yl]-1,3-dioxan-1-yl]thio]-1-(1H-1,2,4-tr-
iazol-1-yl)-2-butanol,
2-(2,4-difluorophenyl)-3-[[1-(4-(trifluoromethoxy)c-
innamoyl]piperidin-4-yl]thio]-1-(1H-1,2,4-triazol-1-yl) -2-butanol,
2-(2,4-difluorophenyl)-3-[[1-[4-nitrocinnamoyl]lpiperidin-4-yl]thio]-1-(1-
H-1,2,4-triazol-1-yl)-2-butanl,
2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol- -1-yl)-3-[[1-
[5-[4-(trifluoromethoxy)phenyl]-2,4-pentadienoyl]piperidin-4-
-yl]thio]-2-butanol,
3-methyl-1-(1H-1,2,4-triazol-1-yl)-2-[4-(trifluoromet-
hyl)phenyl]-3-[[2-[4-(trifluoromethyl)phenyl]-1,3-butadien-1-yl]-1,3-dioxa-
n-5-yl]thio]-2-butanol,
2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-
-[[2-[4-(trifluoromethylthio)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5-yl]th-
io]-2-butanol,
3-[[2-[4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-1,3-butadie-
n-1-yl]-1,3-dioxan-5-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-[4-(trifluoromet-
hyl)phenyl]-2-butanol,
1-(1H-1,2,4-triazol-1-yl)-2-[4-(trifluoromethyl)phe-
nyl]-3-[[2-[4-[4-(trifluoromethyl)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5--
yl]thio]-2-butanol,
2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[2-
-[4-[4-(trifluoromethylsulfinyl)phenyl]-1,3-butadien-1-yl]-1,3
-dioxan-5-yl]thio]-2-butanol,
2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol--
1-yl)-3-[[4-[4-(trifluoromethyl)phenyl]-1,3-butadien-1-yl]-cyclohexyl]thio-
]-2-butanol,
2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[2-[6-[(4-
-(trifluoromethyl)phenyl]-1,3,5-hexatrien-1-yl]-1,3-dioxan-5-yl]thio]-2-bu-
tanol,
2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-3-[[2-[4--
[4-(trifluoromethyl)phenyl]-1,3-butadien-1-yl]-1,3
-dioxan-5-yl]thio]-2-bu- tanol or
2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[2-[4-
[4-(trifluoromethyl)phenyl]-1-buten-3-yn-1-yl]-1,3-dioxan-5-yl]thio]-2-bu-
tanol, or a pharmacologically acceptable salt thereof.
26. An antifungal agent containing the triazole compound or a
pharmacologically acceptable salt thereof according to claims 1 to
25 as an active ingredient.
Description
[0001] This application is a continuation-in-part application of
International application PCT/JP96/00932 filed Apr. 5, 1996, which
is hereby incorporated in its entirety.
[0002] The present invention relates to a 1,2,4-triazole compound
represented by the formula (I) which is particularly effective for
mycotic disease of a human being and an animal.
BACKGROUND OF THE INVENTION
[0003] In the Japanese Unexamined Patent Publication (KOKAI) No.
Sho 61-85369, it is described that an analogous compound of the
compound of the present invention, in which the following moiety
(which corresponds to the right hand moiety of formula (I) which
starts with --A--):
--A--(CO).sub.p--(R.sup.2C.dbd.CR.sup.3).sub.q--(C.ident.C).sub.r--(R.sup.-
4C.dbd.CR.sup.5).sub.s--Ar.sup.2
[0004] is bonded to an alkyl, a cycloalkylalkyl group or a
cycloalkyl group, has antifungal activities.
[0005] However, the present inventors made intensive studies in
order to find a more excellent antifungal agent and found that the
compound of the present invention is an excellent antifungal agent
to accomplish the present invention.
SUMMARY OF THE INVENTION
[0006] The present invention relates to a compound having the
formula 2
[0007] wherein Ar.sup.1 represents a phenyl group or a phenyl group
having 1 to 3 substituent(s), (the substituent(s) represents) a
halogen atom or a trifluoromethyl group);
[0008] Ar.sup.2 represents a phenyl group, a 5- or 6-membered
aromatic heterocyclic group (the aromatic heterocyclic group has at
least one nitrogen, oxygen or sulfur atom) or a phenyl group or a
5- or 6-membered aromatic heterocyclic group having 1 to 3
substituents [the substituent(s) represent(s) a lower alkyl group,
a lower alkoxy group, a halogen atom, a lower alkyl group
substituted with a halogen atom or halogen atoms, a lower alkoxy
group substituted with a halogen atom or halogen atoms, a nitro
group, a cyano group, a --S(O).sub.mR.sup.6 group (R.sup.6
represents a lower alkyl group which may be substituted with a
halogen atom or halogen atoms and m represents 0, 1 or 2) or a
--NHCOR.sup.7 group (R.sup.7 represents a lower alkyl group) and
the aromatic heterocyclic group has at least one nitrogen, oxygen
or sulfur atom];
[0009] R.sup.0 represents a hydrogen atom or a lower alkyl
group;
[0010] R.sup.1 represents a lower alkyl group;
[0011] R.sup.2, R.sup.3, R.sup.4 and R.sup.5 may be the same or
different and represent a hydrogen atom, a lower alkyl group or a
lower alkyl group substituted with a halogen atom or halogen atoms
and, where q and/or s represent 2, each of R.sup.2, R.sup.3,
R.sup.4 and R.sup.5 represents independently a group which is the
same or different from the other R.sup.2, R.sup.3, R.sup.4 and
R.sup.5 respectively;
[0012] n represents 0, 1 or 2;
[0013] p represents 0 or 1;
[0014] q, r and s represent 0, 1 or 2; and
[0015] A represents a 4- to 7-membered aliphatic carbocyclic group
comprising 4 to 7 carbon atoms or a 4- to 7-membered aliphatic
heterocyclic group having at least one nitrogen, oxygen or sulfur
atom, or a pharmacologically acceptable salt thereof.
[0016] The above-mentioned halogen atom is, for example, a
fluorine, chlorine or bromine atom, preferably a fluorine or
chlorine atom.
[0017] The lower alkyl group is, for example, a methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl group,
preferably a methyl, ethyl, propyl or isopropyl group.
[0018] The lower alkoxy group is, for example, a methoxy, ethoxy,
propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy or tert-butoxy
group, preferably a methoxy, ethoxy, propoxy or isopropoxy
group.
[0019] The 5- or 6-membered aromatic heterocyclic group of Ar.sup.2
is, for example, a furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl,
oxazolyl, thiazolyl, pyridyl, pyrimidyl or pyrazyl group,
preferably a furyl, thienyl, pyrrolyl or pyridyl group.
[0020] The 4- to 7-membered aliphatic carbocyclic group comprising
4 to 7 carbon atoms of A is, for example, a cyclobutane,
cyclopentane, cyclohexane or cyclobutane ring, preferably a
cyclobutane, cyclopentane or cyclohexane ring.
[0021] The 4- to 7-membered aliphatic heterocyclic group having at
least one nitrogen, oxygen or sulfur atom of A is, for example, an
azetidine, pyrrolidine, piperidine, homopiperidine, oxetane,
tetrahydrofuran, tetrahydropyran, thietane, tetrahydrothiophene,
pentamethylenesulfide, 1,4,5,6-tetrahydropyrimidine, 1,3-dioxane,
1,3-dithiane, dihydroxazine, tetrahydroxazine, dihydrothiazine or
tetrahydrothiazine ring, preferably an azetidine, piperidine,
1,3-dioxane, 1,4,5,6-tetrahydropyrimidine, tetrahydroxazine or
1,3-dithiane ring.
[0022] The preferable compound having the formula (I) is the
compound in which:
[0023] Ar.sup.1 is a dichlorophenyl, difluorophenyl, chlorophenyl,
fluorophenyl, (trifluoromethyl) phenyl or fluoro (trifluoromethyl)
phenyl group, preferably a 2,4-dichlorophenyl, 2,4-difluorophenyl,
4-chlorophenyl, 4-fluorophenyl, 4-(trifluoromethyl)phenyl or
2-fluoro-4-(trifluoromethyl)phenyl group, particularly preferably a
2,4-dichlorophenyl, 2,4-difluorophenyl or 4-(trifluoromethyl)phenyl
group;
[0024] Ar.sup.2 is a fluorophenyl, chlorophenyl, difluorophenyl,
dicblorophenyl, (trifluoromethyl)phenyl, (trichloromethyl)phenyl,
fluoro-(trifluoromethyl)phenyl, (difluorometoxy)phenyl,
(trifluoromethoxy)phenyl, (2,2,2-trifluoroethoxy)phenyl,
(1,1,2,2-tetrafluoroethoxy)phenyl,
(2,2,3,3-tetrafluoropropoxy)phenyl,
fluoro-(2,2,3,3-tetrafluoropropoxy)phenyl, nitrophenyl,
fluoro-nitrophenyl, cyanophenyl, chloro-cyanophenyl,
(methylthio)phenyl, (methylsulfinyl) phenyl, (methylsulfonyl)
phenyl, (trifluoromethylthio)ph- enyl,
(trifluoromethylsulfinyl)phenyl, (trifluoromethylsulfonyl)phenyl,
chloropyridyl, (trifluoromethyl)pyridyl,
(2,2,3,3-tetrafluoropropoxy)pyri- dyl, (trifluoromethyl)furyl,
chlorothienyl or (trifluoromethyl)thienyl group, preferably a
4-fluorophenyl, 4-chlorophenyl, 2,4-difluorophenyl,
2,4-dichlorophenyl, 4-(trifluoromethyl)phenyl,
4-(trichloromethyl)phenyl, 2-fluoro-4-(trifluoromethyl)phenyl,
4-(difluoromethoxy)phenyl, 3-(trifluoromethoxy)phenyl,
4-(trifluoromethoxy)phenyl, 4-(2,2,2-trifluoroethoxy)phenyl,
4-(1,1,2,2-tetrafluoroethoxy)phenyl,
4-(2,2,3,3-tetrafluoropropoxy)phenyl,
2-fluoro-4-(2,2,3,3-tetrafluoroprop- oxy)phenyl, 4-nitrophenyl,
2-fluoro-4-nitrophenyl, 4-cyanophenyl, 2-chloro-4-cyanophenyl,
4-(methylthio)phenyl, 4-(methylsulfinyl)phenyl,
4-(methylsulfonyl)phenyl, 4-(trifluoromethylthio)phenyl,
4-(trifluoromethylsulfinyl)phenyl,
4-(trifluoromethylsulfonyl)phenyl, 6-chloro-3-pyridyl,
6-(trifluoromethyl)-3-pyridyl, 5-chloro-2-pyridyl,
6-(2,2,3,3-tetrafluoropropoxy)-3-pyridyl,
5-(trifluoromethyl)-2-furyl, 5-chloro-2-thienyl or
5-(trifluoromethyl)-2-thienyl group, particularly preferably a
4-chlorophenyl, 4-(trifluoromethylthio)phenyl,
4-(trifluoromethylsulfonyl)phenyl, 4-(trifluoromethyl)phenyl,
4-(trifluoromethoxy)phenyl or 4-(2,2,3,3-tetrafluoropropoxy)phenyl
group;
[0025] R.sup.0 is a hydrogen atom, a methyl, ethyl or propyl group,
preferably a hydrogen atom, a methyl or ethyl group, particularly
preferably a hydrogen atom or a methyl group;
[0026] R.sup.1 is a methyl, ethyl or propyl group, preferably a
methyl or ethyl group, particularly preferably a methyl group;
[0027] R.sup.2, R.sup.3, R.sup.4 and R.sup.5 may be the same or
different and are a hydrogen atom, a methyl, ethyl, propyl or
trifluoromethyl group, preferably a hydrogen atom, a methyl or
trifluorometbyl group, particularly preferably a hydrogen atom or a
trifluoromethyl group;
[0028] n is 0, 1 or 2, particularly preferably 0;
[0029] p is 0 or 1, particularly preferably 0;
[0030] q is 0, 1 or 2, particularly preferably 1;
[0031] r is 0, 1 or 2, particularly preferably 0 or 1;
[0032] s is 0, 1 or 2, particularly preferably 1;
[0033] A is a cyclobutane, cyclopentane, cyclohexane, azetidine,
pyrrolidine, piperidine, tetrahydrofuran, tetrahydopyran,
tetrahydrothiophene, 1,3-dioxane, 1,3-dithiane, tetrahydroxazine or
tetrahydrothiazine ring, preferably a cyclobutane, cyclohexane,
azetidine, piperidine, 1,3-dioxane, 1,3-dithiane, tetrahydroxazine
or tetrahydrothiazine ring, particularly preferably a cyclohexane,
piperidine, 1,3-dioxane or 1,3-dithiane ring.
[0034] The preferable compound (I) can be exemplified by the
compound in which Ar.sup.1 is a 4-chlorophenyl, 2,4-difluorophenyl,
2,4-dichlorophenyl or 4-(trifluoromethyl)phenyl group; R.sup.0 is a
hydrogen atom or a methyl group; R.sup.1 is a methyl group; and the
moiety represented by the formula:
--S(O).sub.n--A--(CO).sub.p--(R.sup.2C.dbd.CR.sup.3).sub.q--(C.ident.C).su-
b.z--(R.sup.4.dbd.CR.sup.5).sub.s--Ar.sup.2
[0035] is a group as shown in Table 1.
1TABLE 1 Example --S(O).sub.n--A--(CO).sub.p--(R.su-
p.2C.dbd.CR.sup.3).sub.q--(C.ident.C).sub.r--(R.sup.4C.dbd.CR.sup.5).sub.s-
--Ar.sup.2 1 3 2 4 3 5 4 6 5 7 6 8 7 9 8 10 9 11 10 12 11 13 12 14
13 15 14 16 15 17 16 18 17 19 18 20 19 21 20 22 21 23 22 24 23 25
24 26 25 27 26 28 27 29 28 30 29 31 30 32 31 33 32 34 33 35 34 36
35 37 36 38 37 39 38 40 39 41 40 42 41 43 42 44 43 45 44 46 45 47
46 48 47 49 48 50 49 51 50 52 51 53 52 54 53 55 54 56 55 57 56 58
57 59 58 60 59 61 60 62 61 63 62 64 63 65 64 66 65 67 66 68 67 69
68 70 69 71 70 72 71 73 72 74 73 75 74 76 75 77 76 78 77 79 78 80
79 81 80 82 81 83 82 84 83 85 84 86 85 87 86 88 87 89 88 90 89 91
90 92 91 93 92 94 93 95 94 96 95 97 96 98 97 99 98 100 99 101 100
102 101 103 102 104 103 105 104 106 105 107 106 108 107 109 108 110
109 111 110 112 111 113 112 114 113 115 114 116 115 117 116 118 117
119 118 120 119 121 120 122 121 123 122 124 123 125 124 126 125 127
126 128 127 129 128 130 129 131 130 132 131 133 132 134 133 135 134
136 135 137 136 138 137 139 138 140 139 141 140 142 141 143 142 144
143 145 144 146 145 147 146 148 147 149 148 150 149 151 150 152 151
153 152 154 153 155 154 156 155 157 156 158 157 159 158 160 159 161
160 162 161 163 162 164 163 165 164 166 165 167 166 168 167 169 168
170 169 171 170 172 171 173 172 174 173 175 174 176 175 177 176 178
177 179 178 180 179 181 180 182 181 183 182 184 183 185 184 186 185
187 186 188 187 189
[0036] Preferred compounds in Table 1 include those having the
substituents of 4, 6, 7, 13, 16, 18, 22, 25, 32, 36, 40, 43, 44,
47, 52, 53, 61, 63, 71, 76, 96, 107, 123, 127, 142, 174, 176, 177,
178, 181, 182, 183 and 186, and particularly preferable compounds
may include
[0037]
2-(2,4-difluorophenyl)-3-[[2-[2-[4-(trifluoromethyl)phenyl]vinyl]-1-
,3-dioxan-5-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol (the
compound corresponding to Example 2),
[0038]
2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[2-[2-[4-(trifl-
uoromethoxy)phenyl]vinyl]-1,3-dioxan-5-yl]thio]-2-butanol (the
compound corresponding to Example 11),
[0039]
2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[2-[4-[4-(trifl-
uoromethyl)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-2-butanol
(the compound corresponding to Example 15),
[0040]
2-(2,4-difluorophenyl)-3-[[2-[4-[4-(2,2,3,3-tetrafluoropropoxy)phen-
yl]-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-b-
utanol (the compound corresponding to Example 16),
[0041] 2-(2,4-difluorophenyl)
-3-[[2-[4-[4-(chlorophenyl)-4,4,4-trifluoro--
1,3-pentadien-1-yl]-1,3-dioxan-1-yl]thio]-1-(1H-1,2,4-triazol-1-yl)
-2-butanol (the compound corresponding to Example 18),
[0042] 2-(2,4-difluorophenyl)-3-[[1-[4-
(trifluoromethoxy)cinnamoyl]piperi-
din-4-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol (the compound
corresponding to Example 21),
[0043] 2-
(2,4-difluorophenyl)-3-[[1-[4-nitrocinnamoyl]piperidin-4-yl]thio-
]-1-(1H-1,2,4-triazol-1-yl) -2-butanol (the compound corresponding
to Example 23),
[0044] 2-
(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[1-[5-[4-(trif-
luoromethoxy)phenyl]-2,4-pentadienoyl]piperidin-4-yl]thio]-2-butanol
(the compound corresponding to Example 24),
[0045]
3-methyl-1-(1H-1,2,4-triazol-1-yl)-2-[4-(trifluoromethyl)phenyl]-3--
[[2-[4-(trifluoromethyl)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-2-
-butanol (the compound corresponding to Example 31),
[0046]
2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[2-[4-(trifluor-
omethylthio)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-2-butanol
(the compound corresponding to Example 32),
[0047]
3-[[2-[4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-1,3-butadien-1-yl]--
1,3-dioxan-5-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-[4-(trifluoromethyl)phen-
yl]-2 -butanol (the compound corresponding to Example 33),
[0048]
1-(1H-1,2,4-triazol-1-yl)-2-[4-(trifluoromethyl)phenyl]-3-[[2-[4-[4-
-(trifluoromethyl)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-2-butan-
ol (the compound corresponding to Example 34),
[0049]
2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[2-[4-[4-(trifl-
uoromethylsulfinyl)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-2-buta-
nol (the compound corresponding to Example 35),
[0050] 2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)
-3-[[4-[4-(trifluoromethyl)phenyl]-1,3-butadien-1-yl]-cyclohexyl]thio]-2--
butanol (the compound corresponding to Example 36),
[0051]
2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[2-[6-[4-(trifl-
uoromethyl)phenyl]-1,3,5-hexatrien-1-yl]-1,3-dioxan-5-yl]thio]-2-butanol
(the compound corresponding to Example 37),
[0052]
2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-3-[[2-[4--
[4-(trifluoromethyl)phenyl]-1,3
-butadien-1-yl]-1,3-dioxan-5-yl]thio]-2-bu- tanol (the compound
corresponding to Example 38) and
[0053]
2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[2-[4-[4-(trifl-
uoromethyl)phenyl]-1-buten-3-yn-1-yl]-1,3-dioxan-5-yl]thio]-2-butanol
(the compound corresponding to Example 39).
[0054] The triazole compound (I) of the present invention has at
least two asymmetric carbon atoms, and optical isomers and
diastereomers exist. In the optical isomer, both antipodes can be
obtained by general optical resolution or asymmetric synthesis.
Further, the diastereomers can be separated by conventional
separation methods such as fractional recrystallization and
chromatography. The compound (I) of the present invention includes
one of these isomers or mixtures thereof.
[0055] The triazole compound (I) of the present invention can be
used as an antifungal agent as such or in the form of a
pharmacologically acceptable salt. The pharmacologically acceptable
salt of the compound (I) includes, for example, a salt of inorganic
acids such as hydrochloric acid, hydrochloric acid, sulfuric acid
and nitric acid, a salt of carboxylic acids such as acetic acid,
fumaric acid, maleic acid, oxalic acid, malonic acid, succinic
acid, citric acid and malic acid, a salt of sulfonic acids such as
methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and
toluenesulfonic acid and a salt of amino acids such as glutamic
acid and aspartic acid, preferably a salt of carboxylic acids.
[0056] Incidentally, a hydrate of the compound (I) and a hydrate of
the salt of the compound (I) are also included in the compound of
the present invention.
[0057] The compound (I) and a pharmacologically acceptable salt
thereof of the present invention exhibit excellent antifungal
activities and in the case where the compound (I) and a
pharmacologically acceptable salt thereof are used as an antifungal
agent, they can be administered as such or as a mixture, for
example, with a suitable pharmacologically acceptable excipient or
diluent orally in the form of a tablet, a capsule, a granule, a
powder or a syrup or parenterally in the form of injection
preparations.
[0058] These preparations are prepared by the known method using
additives such as excipients (for example, sugar derivatives such
as lactose, sucrose, glucose, manitol and sorbitol; starch
derivatives such as corn starch, mashed potato starch,
.alpha.-starch, dextrine and carboxymethyl starch; cellulose
derivatives such as crystalline cellulose, low
hydroxypropyl-substituted cellulose, hydroxypropylmethyl cellulose,
carboxymethyl cellulose, carboxymethyl cellulose calcium and
internally bridged carboxymethyl cellulose sodium; gum arabic;
dextran; Pullulan; silicate derivatives such as light silicic acid
anhydride, synthetic aluminum silicate and magnesium meta-silicic
acid aluminate; phosphate derivatives such as calcium phosphate;
carbonate derivatives such as calcium carbonate; and sulfate
derivatives such as calcium sulfate), binders (for example, the
above excipients; gelatin; polyvinylpyrrolidone; and Macrogol);
disintegrating agents (for example, the above excipients;
chemically modified starch-cellulose derivatives such as
Crosscarmelose sodium, sodium carboxymethyl starch and bridged
polyvinylpyrrolidone), lubricants (for example, talc; stearic acid;
and metal stearates such as calcium stearate and magnesium
stearate; colloidal silica; waxes such as beeswax and spermaceti;
boric acid; glycol; carboxylic acid such as fumaric acid and adipic
acid; sodium carboxylate such as sodium benzoate; sulfates such as
sodium sulfate; leucine; lauryl sulfates such as sodium
laurylsulfate and magnesium laurylsulfate; silicic acids such as
silicic acid anhydride and silicic acid hydrate; and starch
derivatives in the above excipients), stabilizers (for example,
p-hydroxybenzoates such as methylparaben and propylparaben;
alcohols such as chlorobutanol, benzyl alcohol and phenylethyl
alcohol; benzalkonium chloride; phenols such as phenol and cresol;
thimerosal; acetic anhydride; and sorbic acid); corrigents (for
example, sweeteners, sour agents and perfumes conventionally used),
suspending agents (for example, polysorbate 80 and carboxymethyl
cellulose sodium), diluents and solvents for preparations (for
example, water, ethanol and glycerin). While the dose varies
depending on the condition and age of the patient to be treated, it
is desirably administered 1 to 6 times daily depending on the
condition: in the case of oral administration, the lower limit of 1
mg each time (preferably 5 mg) and the upper limit of 2000 mg
(preferably 1000 mg) for an adult; and in the case of intravenous
administration, the lower limit of 0.1 mg each time (preferably 0.5
mg) and the upper limit of 600 mg (preferably 500 mg) for an
adult.
[0059] Among the compounds having the formula (I) of the present
invention, the compound (Ia) in which R.sup.0 is a hydrogen atom
and n=0 can be prepared according to the process shown below:
190
[0060] (wherein Ar.sup.1 and R.sup.1 have the same meanings as
defined above and R.sup.8 represents the formula:
--A--(CO).sub.p--(R.sup.2C.dbd.CR.sup.1).sub.q--(C.ident.C).sub.r--(R.sup.-
4C.dbd.CR.sup.5).sub.s--Ar.sup.2
[0061] described above). More specifically, the desired compound
(Ia) is prepared by reacting an epoxide compound (2) described in
Japanese Unexamined Patent Publication (KOKAI) No. Hei 2-191262
(Jul. 27, 1990) with mercaptan (3) or an acetic acid ester
derivative thereof under basic conditions. The solvent employable
in the reaction includes preferably alcohols such as methanol,
ethanol and propanol, aprotic solvents such as dimethylformamide,
dimethylacetamide, dimethyl sulfoxide, acetonitrile and
tetrahydrofuran. However, in the case where the reaction is carried
out in the above aprotic solvent using an acetyl derivative (4), it
is required to coexist alcohols or water. The base employable in
the reaction includes sodium hydride, sodium methoxide, sodium
ethoxide, lithium methoxide, potassium tert-butoxide, lithium
hydroxide, sodium hydroxide and potassium hydroxide. The amount to
be used is 0.1 to 2 molar equivalents based on the compound (2).
Mercaptan (3) or the acetic acid derivative thereof (4) is used in
1 to 3 molar equivalents. The reaction temperature is room
temperature to 100.degree. C. and the reaction time is 2 to 10
hours. The compound (Ia) can be obtained by treating the reaction
mixture by conventional procedures (an oil obtained by extraction
with an organic solvent and then evaporation of the solvent is
purified by column chromatography or recrystallization).
[0062] Incidentally, R.sup.8SH (3) or R.sup.8SAc (4) used in the
above reaction can be obtained according to the process shown
below. More specifically, the compound (3) or (4) in which A in
R.sup.8 is a 1,3-dioxane rig and p=0 can be prepared using the
known compound (5) [reference: O. E. van Lobuizen, P. E. Verkade,
Rec. trav. chim., 78, 460 (1959)] as a starting material according
to the scheme shown below (with respect to the reaction conditions
and the isolation method in eacl step, see Reference examples 3, 4,
5, 6 and 7): 191
[0063] (wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5, Ar.sup.2, q, r
and s have the same meanings as defined above). Among the
unsaturated aldehydes (6) used in the above reaction, the coumpound
(6a) in which r=0 can be generally obtained through an unsaturated
ester (7a) according to the process shown below (with respect to
the reaction conditions and the isolation method in each step, see
Reference examples 8, 9, 10, 20, 21, 22, 23, 33 and 49): 192
[0064] (wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5, Ar.sup.2, q and
s have the same meanings as defined above and DIBAL-H represents
diisobutyl aluminum hydride).
[0065] Among the unsaturated aldebydes (6), the compound (6b) in
which r=1 or 2 can be generally obtained through an unsaturated
ester (7b) according to the process shown below (with respect to
the reaction conditions and the isolation method in each step, see
Reference examples 44, 45, 46, 47 and 48): 193
[0066] (wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5, q, r and s have
the same meanings as defined above and DIBAL-H represents
diisobutyl aluminum hydride).
[0067] Further, the compound (3b) or (4b) in which A in R.sup.8 of
R.sup.8SH (3) or R.sup.8SAc (4) is a 4- to 7-membered
nitrogen-containing heterocyclic group (azetidine, pyrrolidine,
piperidine, homopiperidine) and p=1 can be obtained according to
the process shown below (with respect to the reaction conditions
and the isolation method in each step, see Reference examples 16
and 17): 194
[0068] (wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5, q, r and s have
the same meanings as defined above, t represents 3, 4, 5 or 6 and
Boc represents tert-butoxycarbonyl).
[0069] The acid chloride (10) used in the above reaction can be
obtained by treating a carboxylic acid, obtained by
alkali-decomposing the unsaturated ester (7a) or (7b) described
above, with thionyl chloride.
[0070] Among the compounds having the formula (I) of the present
invention, the compound (Ia) in which R.sup.0 is a hydrogen atom
and n=0 can be also obtained according to the process shown below
195
[0071] (wherein Ar.sup.1, R.sup.1 and R.sup.8 have the same
meanings as defined above and X represents a chlorine, bromine or
iodine atom, methanesulfonyloxy, benzenesulfonyloxy or
toluenesulfonyloxy). More specifically, the process is to prepare
the desired compound (Ia) by reacting a triazolylmercapto alcohol
derivative (11) described in Japanese Unexamined Patent Publication
(KOKAI) No. Hei 3-240778 (Oct. 28, 1991) with an alkylating agent
(12) under basic conditions. The solvent employable in the reaction
includes methanol, ethanol, propanol, butanol, dimethylformamide,
dimethylacetamide, dimethyl sulfoxide, acetonitrile,
tetrahydrofuran, dioxane, diethyl ether, acetone, benzene, toluene,
xylene, etc. The base employable in the reaction includes
triethylamine, diisopropylethylamine, sodium hydride, sodium
methoxide, sodium ethoxide, lithium methoxide, potassium
tert-butoxide, sodium hydroxide, potassium hydroxide, etc., and the
amount used is 1 to 3 molar equivalents based on the compound (11).
The alkylating reagent(12)is used in 1 to 3 molar equivalents. The
reaction temperature is -50 to 100.degree. C. and the reaction time
is 2 to 10 hours. The compound (Ia) can be obtained by treating the
reaction mixture by conventional procedures (an oil obtained by
extraction with an organic solvent and then evaporation of the
solvent is purified by column chromatography or
recrystallization).
[0072] The alkylating reagent R.sup.8-X (12) used in the above
reaction can be obtained according to the process shown below. The
compound (12a) in which A in R.sup.8 is a 1,3-dioxane ring and p=0
can be obtained, for example, by reacting a diol compound (13),
obtained by treating the above compound (5) with an acid in
methanol, with the above unsaturated aldehyde (6) under acidic
conditions (Reference example Nos. 56 and 57): 196
[0073] (wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5, Ar.sup.2, q, r
and s have the same meanings as defined above). Further, the
compound (12b) in which A in R.sup.8 is a 4- to 7-membered
nitrogen-containing heterocyclic group (azetidine, pyrrolidine,
piperidine, homopiperidine) and p=1 can be obtained, for example,
by reacting a compound (14) obtained by treating the above cyclic
amine derivative (8) with HCl, with the above acid chloride (10) in
the presence of a base such as triethylamine: 197
[0074] (wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5, Ar.sup.2, q, r,
s and t have the same meanings as defined above).
[0075] Among the compounds having the formula (I) of the present
invention, the compound (lb) in which R.sup.0 is a hydrogen atom,
n=0, p=0 and A is a 1,3-dioxane ring can be also prepared according
to the process shown below: 198
[0076] (wherein Ar.sup.1, Ar.sup.2, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, p, q and r have the same meanings as defined
above). More specifically, the process is to prepare the desired
coound (Ib) by reacting the above epoxide compound (2) with a
thioacetic acid derivative (15) obtained by the reaction of the
above known compound (5) with sodium thioacetate under the same
conditions as in the reaction of (2) and (4) to obtain the cound
(16), deprotecting the copound (1) according to conventional
procedures such as the treatment with an acid to obtain the
compound (17) and reacting the compound (17) with the above
aldehyde compound (6). The reaction of the compounds (17) and (6)
is usually carried out under acidic conditions. The acid employable
here includes, for example, hydrogen chloride, sulfuic acid, nitric
acid, boron trifluoride, methanesulfonic acid, benzenesulfonic acid
and p-toluenesulfonic acid and the amount of the acid used is 1 to
2 molar equivalents based on (17). The aldehyde (6) is used in 1 to
2 molar equivalents. As the solvent, aprotic solvents such as
methylene chloride, chloroform, 1,2 -dichloroethane, benzene,
toluene, xylene, diethyl ether and tetrahydofuran are used. The
reaction is carried out in the range of 0.degree. C. to a boiling
point of the solvent and the reaction time is 2 to 10 hours While
water produced by the reaction can be removed by azeotroic
distillation, molecular sieves may be used as a dehydrating agent.
The compound (Ib) can be obtained by neutralizing the reaction
mixture with an aqueous sodium bydrogencarbonate solution and then
treating it by conventional procedures (an oil obtained by
extraction with an organic solvent and then evaporation of the
solvent is purified by column chromatography or
recrystallization).
[0077] Among the compounds of the present invention, the compound
(Ic) in which R.sup.0 is a hydrogen atom, n=0, p=1 and A is a 4- to
7-membered nitrogen-containing heterocyclic group (azetidine,
pyrrolidine, piperidine, bomopiperidine) can be obtained according
to the process shown below: 199
[0078] (wherein Ar.sup.1, Ar.sup.2, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, q, r, s and t have the same meanings as defined
above and Boc represents tert-butoxy carbonyl). More specifically,
the process is to prepare the desired compound (Ic) by reacting the
above epoxide compound (2) with the mercaptan compound (18),
obtained by treating the above thioacetic acid derivative (9) with
an alkali, under the same conditions as in the reaction of (2) and
(3) to obtain the compound (19), deprotecting (19) by treating it
with an acid according to conventional procedures to obtain the
compound (20) and reacting the compound (20) with the above acid
chloride (10). The reaction of compounds (20) and (10) is carried
out in an inert solvent such as benzene, toluene, methylene
chloride, chloroform or tetrahydrofuran in the presence of an
appropriate base by conventional procedures (Reference example Mos.
13, 14, 18 and 19).
[0079] Among the compounds (I) of the present invention, the
compound in which n=1 or n=2 can be prepared according to the
process mentioned below. More specifically, the compound (I) in
which n=1 can be prepared by oxidizing the compound (I) in which
n=0 obtained by the above process in a solvent using 1 equivalent
of an oxidizing agent, and the compound (I) in which n=2 can be
prepared by oxidizing it using 2 or more equivalents of an
oxidizing agent. The solvent employable here is not particularly
limited so long as it does not inhibit the reaction and dissolves
the starting materials to some extent and may include preferably a
halogenated bydrocarbon such as methylene chloride and chloroform.
The oxidizing agent employable here may include, for example,
peracetic acid and 3-chloroperbenzoic acid. The reaction is carried
out at 0 to 50.degree. C., preferably at room temperature, and the
reaction time is usually 30 minutes to 2 hours. The compound (I)
(n=1 or 2) can be obtained by treating the reaction mixture
according to conventional procedures (after the reaction mixture is
washed with aqueous sodium hydrogencarbonate, the crude product
obtained by evaporation of the solvent is purified by
chromatography or recrystallization).
[0080] Among the compounds having the formula (I) of the present
invention, the compound (Id) in which R.sup.0 is lower alkyl and
n=0 can be prepared according to the process shown below: 200
[0081] (wherein Ar.sup.1, R.sup.0, R.sup.1 and R.sup.8 have the
same meanings as defined above). More specifically, the desired
compound (Id) is prepared by reacting bromoketone (21), obtained
according to the procedures described in Japanese Unexamined Patent
Publication (KOKAI) No. Hei 7-2802 (Jan. 6, 1995), with the above
mercaptan (3) or an acetic acid derivative thereof (4) under
alkaline conditions to obtain a thioether derivative (22) and
reacting (22) with trimethylsulfoxonium iodide and 1,2,4-triazole
in the presence of a base. The solvent used in the reaction of (21)
and (3) or (4) includes preferably alcohols such as methanol,
ethanol and propanol, and the alkli employable here includes sodium
hydroxide, potassium hydroxide, sodium methoxide and sodium
ethxide. The solvent used in the reaction for converting the
thioether derivative (22) to (Id) includes preferably alcohols such
as methanol, ethanol, propanol, butanol and t-butanol and aprotic
solvents such as dimethylformamide, dimethylacetamide, dimethyl
sulfoxide, acetonitrile and tetrahydrofuran. The base used in the
reaction includes sodium hydride, sodium methoxide, sodium
ethoxide, lithium methoxide, potassium tert-butoxide, lithiu
hydroxide, sodium hydroxide and potassium hydroxide, and the amount
used is 2 to 5 molar equivalents based on the compound (22).
Trimethylsulfoxonium iodide and 1,2,4-triazole are used in 1 to 2
molar equivalents based on the compound (22), respectively. The
reaction temperature is room temperature to 100.degree. C. and the
reaction time is 2 to 10 hours. The compound (Id) (n=0) can be
obtained by treating the reaction mixture by conventional
procedures (a crude product obtained by extraction with an organic
solvent and then evaporation of the solvent is purified by column
chromatography or recrystallization). Among the compounds (I), the
compound (Ie) in which n=0, p=0 and A is a 1,3-dioxane ring can be
obtained from the compound (23) in which R.sup.8 is a group
represented by the formula: 201
[0082] in the compound (Id) obtained by the above process through a
triol (24) according to the process shown below: 202
[0083] (wherein R.sup.0 represents lower alkyl and Ar.sup.1,
Ar.sup.2, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, q, r and s
have the same meanings as defined above). The reaction conditions
in the above respective steps are the same as those described in
the reaction of (16).fwdarw.(17).fwdarw.(Ib).
[0084] The present invention will be explained below in more detail
by referring to Examples, Reference examples, Test examples and
Preparation examples but the scope of the present invention is not
limited thereto.
[0085] Incidentally, the aldehyde compounds used in Examples are
synthesized according to the procedures described in the literature
and/or the citation of the literature in the cases where the
literature is indicated in parenthesis. The aldehyde compounds for
which the literature is not indicated are commercially available or
can be obtained by the procedures for synthesizing an aldehyde
which are described in the literature in the parenthesis of
Examples or are described in the citation of the literature or a
process according to the procedures for synthesizing an aldehyde
described in Reference example of the present specification.
[0086] [Best mode for practicing the invention]
EXAMPLE 1
(2R,3R)-2-(2,4-Difluorophenyl)-3-[[trans-2-[(E)-1-methyl-2-[4-(trifluorome-
tbyl)phenyl]vinyl]-1,3-dioxan-5-yl]thio]-2-butanol
[0087] 203
[0088] In 2 ml of dimethylformamide were dissolved 166 mg (0.48
mmol) of
trans-4-(acetylthio)-2-[(E)-1-methyl-2-[4-(trifluoromethyl)phenyl]vinyl]--
1,3-dioxane as described in Reference example 7 and 110 mg (0.44
mmol) of
(2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]-
oxirane, and 0.15 ml (0.24 mmol) of a 1.6M sodium
methoxide-methanol solution were added thereto under nitrogen
atmosphere, followed by stirring of the resulting mixture at
55.degree. C. for 6 hours. After cooling, ethyl acetate was added
to the reaction mixture to dilute it and the resulting mixture was
washed with a saturated aqueous NaCl solution. An oil obtained by
distilling off the solvent was subjected to column chromatography
using 15 g of silica gel and was eluted by a mixed solvent of
hexane-ethyl acetate (2:1) to obtain 180 mg (yield: 74%) of the
desired compound as an oil.
[0089] NMR spectrum (60 MHz, CDCl.sub.3) .delta. ppm: 1.19 (3H, d,
J=7 Hz), 1.90 (3H, d, J=1.5 Hz), 3.34 (1H, q, J=7 Hz), 3.0-3.9 (3H,
m), 4.1-4.6 (2H, m), 4.80 (1H, d, J=14 Hz), 4.94 (1H, s), 5.02 (1H,
d, J=1 Hz), 5.05 (1H, d, J=14 Hz), 6.4-7.0 (3H, m), 7.1-7.6 (1H,
m), 7.40 (2H, d, J=9 Hz), 7.62 (2H, d, J=9 Hz), 7.80 (2H, s).
EXAMPLE 2
(2R,3R)-2-(2,4-Difluorophenyl)-3-[[trans-2-[(E)-2-[4-(trifluoromethyl)phen-
yl]vinyl]-1,3-dioxan-5-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol
[0090] 204
[0091] Reaction and treatment were carried out in the same manner
as in Example 1 using
(2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-tria-
zol-1-yl)methyl]oxirane and
trans-5-(acetylthio)-2-[(E)-2-[4-(trifluoromet-
hyl)phenyl]vinyl]-1,3-dioxane to obtain the desired compound having
a melting point of 73 to 75.degree. C. in a yield of 70%.
[0092] Specific rotation [.alpha.].sub.D.sup.25-73.8.degree.
(c=1.00, CHCl.sub.3)
[0093] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.19 (3H, d,
J=7.3 Hz), 3.34 (1H, q, J=7.3 Hz), 3.43 (H, tt, J=11.2, 4.6 Hz),
3.65 (1H, t, J=11.2 Hz), 3.67 (1H, t, J=11.2 Hz), 4.33 (1H, ddd,
J=11.2, 4.6, 2.0 Hz), 4.46 (1H, ddd, J=11.2, 4.6, 2.0 Hz), 4.82
(1H, d, J=13.8 Hz), 5.03 (1H, d, J=13.8 Hz), 5.04 (1H, br s), 5.14
(1H, d, J=4.6 Hz), 6.25 (1H, dd, J=15.8, 4.6 Hz), 6.7-7.8 (2H, m),
6.83 (1H, d, J=15.8 Hz), 7.3-7.45 (1H, m), 7.49 (2H, d, J=8.6 Hz),
7.58 (2H, d, J=8.6 Hz), 7.79 (2H, s).
EXAMPLE 3
(2R,3R)-3-[[Trans-4-[(E)-2-(4-chlorophenyl)vinyl]cyclohexyl]thio]-2-(2,4-d-
ifluorophenyl)-1-(1H-1,2,4-triazol-1-yl) -2 -butanol
[0094] 205
[0095] Reaction and treatment were carried out in the same manner
as in Example 1 using
(2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-tria-
zol-1-yl)methyl]oxirane and
trans-1-(acetylthio)-4-[(E)-2-(4-chlorophenyl)- vinyl]cyclohexane
to obtain the desired compound having a melting point of 64 to
66.degree. C. in a yield of 31%.
[0096] Specific rotation [.alpha.].sub.D.sup.25 -84.1.degree.
(c=2.69, CHCl.sub.3)
[0097] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.16 (3H, d,
J=7.3 Hz), 1.2-1.6 (4H, m), 1.9-2.0 (2H, m), 2.1-2.25 (3H, m), 2.70
(1H, tt, J=11.2, 4.0 Hz), 3.36 (1H, q, J=7.3 Hz), 4.60 (1H, s),
4.83 (1H, d, J=13.9 Hz), 5.10 (1H, d, J=13.9 Hz), 6.11 (1H, dd,
J=15.8, 7.3 Hz), 6.32 (1H, d, J=15.8 Hz), 6.74 (2H, t-like, J=9
Hz), 7.26 (4H, s), 7.37 (1H, td, J=8.6, 6.5 Hz), 7.76 (1H, s), 7.83
(1H, s).
EXAMPLE 4
(2R,3R) -3-
[[Trans-2-[(E)-2-(4-chLlorophenyl)vinyl]-1,3-dioxan-5-yl]thio]-
-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol
[0098] 206
[0099] In 14 ml of methylene chloride were dissolved 294 mg (0.82
mmol) of
(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2-
,4-triazol-1-yl)-2-butanol as described in Reference examuple 2 and
191 mg (1.15 mmol) of trans-4-chlorocinnamaldehyde [Bull. Chem.
Soc. Japan 52 555 (1979], and 233 mg (1.23 mmol) of
p-toluenesulfonic acid monohydrate and 1.5 g of molecular sieves 4A
were added thereto, followed by stirring of the resulting mixture
for 1 hour and 15 minutes. An aqueous sodium hydrogencarbonate
solution was added to the reaction mixture and the mixture was
stirred for 10 minutes, followed by removal of the molecular sieves
by filtration. The organic layers were collected and dried to
distil off the solvent under reduced pressure. The thus obtained
oil was subjected to column chromatography using 15 g of silica gel
and eluted with a mixed solvent hexane-ethyl acetate (3:2) to
obtain 280 mg (yield: 67%) of the desired title compound, trans
isomer (A) as an oil. Further, the oil was eluted with a mixed
solvent of hexane-ethyl acetate (1:1) to obtain 35 mg (yield: 8%)
of the cis isomer (B) as an oil.
[0100] Specific rotation (A) [.alpha.].sub.D.sup.25 -68.degree.
(c=1.22, CHCl.sub.3)
[0101] Specific rotation (B) [.alpha.].sub.D.sup.25 -80.degree.
(c=1.30, CHCl.sub.3)
[0102] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: (A), 1.19
(3H, d, J=7.3 Hz), 3.34 (1H, q, J=7.3 Hz), 3.41 (1H, tt, J=11.2,
4.6 Hz), 3.64 (1H, t, J=11.2 Hz), 3.66 (1H, t, J=11.2 Hz), 4.32
(1H, ddd, J=11.2, 4.6, 2.6 Hz), 4.44 (1H, ddd, J=11.2, 4.6, 2.6
Hz), 4.82 (1H, d, J=13.9 Hz), 5.01 (1H, s), 5.04 (1H, d, J=13.9
Hz), 5.11 (1H, d, J=4.6 Hz), 6.15 (1H, dd, J=15.8, 4.6 Hz), 6.7-6.8
(2H, m), 6.76 (1H, d, J=15.8 Hz), 7.25-7.45 (5H, m), 7.78 (2H, s);
(B), 1.21 (3H, d, J=7.3 Hz), 3.11 (1H, s-like), 3.50 (1H, q, J=7.3
Hz), 4.2-4.4 (4H, m), 4.88 (1H, J=14.5 Hz), 4.93 (1H, s), 5.16 (1H,
d, J=14.5 Hz), 5.23 (1H, d, J=4.6 Hz), 6.21 (1H, dd, J=16.5, 4.6
Hz), 6.65-6.8 (2H, m), 6.76 (1H, d, J=16.5 Hz), 7.25-7.45 (5H, m),
7.77 (1H, s), 7.80 (1H, s).
[0103] In ethyl acetate was dissolved 54 mg of (A), and 19 mg of
oxalic acid was added to the solution, followed by addition of
hexane to the resulting mixture. The precipitated cystal was
collected by filtration to obtain 65 mg of the oxalic acid salt
having a melting point of 89 to 92.degree. C. The oxalate of (B)
having a melting point of 94 to 98.degree. C. was obtained
analogously.
EXAMPLE 5
(2R,3R)-2-(2,4-Difluorophenyl)-3-[[trans-2-[(E)-2-(3-pyridyl)vinyl]-1,3-di-
oxan-5-yl]thio]-1-(1H-1,2,4-triazol-1-yl) -2-butanol
[0104] 207
[0105] In 5 ml of methylene chloride were dissolved 120 mg (0.33
mmol) of
(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2-
,4-triazol-1-yl)-2-butanol and 60 mg (0.45 mmol) of
trans-.beta.-(3-pyridyl)acrolein [J. Med. Chem. 18 839 (1975)], 190
mg (1.00 mmol) of p-toluenesulfonic acid monohydrate and 1.2 g of
molecular sieves 4A were added to the solution, followed by
stirring of the resulting mixture for 1 hour and 15 minutes. An
aqueous sodium hydrogencarbonate solution was added to the reaction
mixture and the mixture was stirred for 10 minutes, followed by
removal of the molecular sieves by filtration and extraction with
chloroform. An oil obtained by evaporation of the solvent after
drying was subjected to column chromatography using 15 g of silica
gel and eluted with a mixed solvent of hexane-ethyl acetate (1:4 to
1:5) to obtain 82 mg (yield: 52%) of the title compound, trans
isomer (A) as an oil. Further, the oil was eluted with ethyl
acetate-5% methanol-ethyl acetate to obtain 28 mg (yield: 15%) of
the cis isomer (B) having a melting point of 118 to 125.degree. C.
as a solid.
[0106] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: (A), 1.20
(3H, d, J=7.3 Hz), 3.34 (1H, q, J=7.3 Hz), 3.43 (1H, tt, J=11.2,
4.6 Hz), 3.65 (1H, t, J=11.2 Hz), 3.68 (1H, t, J=11.2 Hz), 4.33
(1H, m), 4.46 (1H, m), 4.83 (1H, d, J=13.9 Hz), 5.04 (1H, s), 5.04
(1H, d, J=13.9 Hz), 5.14 (1H, d, J=4.0 Hz), 6.25 (1H, dd, J=16.5,
4.0 Hz), 6.7-6.8 (2H, m), 6.81 (1H, d, J=16.5 Hz), 7.29 (1H, dd,
J=7.9, 4.6 Hz), 7.3-7.45 (1H, m), 7.73 (1H, dt, J=7.9, 1 Hz),8.51
(1H, dd, J-4.6, 1 Hz), 8.62 (1H, d, J=1 Hz); (B), 1.22 (3H, d,
J=7.3 Hz), 3.13 (1H, br s), 3.50 (1H, q, J=7.3 Hz), 4.2-4.4 (4H,
m), 4.88 (1H, d, J=13.9 Hz), 4.94 (1H, s), 5.17 (1H, d, T=13.9 Hz),
5.26 (1H, d, J=4.6 Hz), 6.31 (1H, dd, J=16.5, 4.6 Hz), 6.65-6.8
(2H, m), 6.81 (1H, d, J=16.5 Hz), 7.26 (1H, dd, J=7.9, 4.6 Hz),
7.74 (1H, td, J=7.2, 6.6 Hz), 7.74 (1H, br d, J=7.9 Hz), 7.77 (1H,
s), 7.80 (1H, s), 8.50 (1H, br d, J=4.6 Hz), 8.63 (1H, br s).
EXAMPLE 6
(2R,3R)-2-(2,4-Difluorophenyl)-3-[[trans-2-[(E)-2-[4-(trifluoromethyl)phen-
yl]vinyl]-1,3-dioxan-5-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol
[0107] 208
[0108] Reaction and treatment were carried out in the same manner
as in Example 4 using
(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl-
)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol and
trans-4-(trifluoromethyl)ci- nnamaldehyde as described in Reference
example 22 to obtain the desired compound as a major product
(yield: 62%). Physical data and spectral data coincided with those
of the compound described in Example 2.
EXAMPLE 7
(2R,3R)-2-(2,4-Difluorophenyl)-3-[[trans-2-[(E)-2-(4-fluorophenyl)vinyl]-1-
,3-dioxan-5-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol
[0109] 209
[0110] Reaction and treatment were carried out in the same manner
as in Example 4 using
(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl-
)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol and
trans-4-fluorocinnamaldehyd- e [Arch. Pharm. 316 574 (1983)] to
obtain the title compound, a major product as an oil in a yield of
66%.
[0111] NMR spectrum (60 MHz, CDCl.sub.3) .delta. ppm: 1.20 (3H, d,
J=7 Hz), 3.1-3.9 (4H, m), 4.1-4.6 (2H, m), 4.78 (1H, d, J=14 Hz),
4.99 (1H, d, J=1.5 Hz), 5.06 (1H, d, J=14 Hz), 5.09 (1H, d, J=4
Hz), 6.07 (1H, dd, J=16.4 Hz), 6.79 (1H, d, J=16 Hz), 6.5-7.6 (7H,
m), 7.78 (2H, 6).
[0112] This compound was mixed with 1 equivalent of oxalic acid in
a mixed solvent of ethyl acetate-hexane to obtain an oxalic acid
salt crystal having a melting point of 132 to 135.degree. C.
EXAMPLE 8
(2R,3R)-2-(2,4-Difluorophenyl)-3-[[trans-2-[(E)-2-[2-fluoro-(4-trifluorome-
thyl)phenyl]vinyl]-1,3-dioxan-5-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butan-
ol
[0113] 210
[0114] Reaction and treatment were carried out in the same manner
as in Example 4 using
(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl-
)thio]-1-(1H-1,2,4-triazol-5-yl)-2-butanol and
trans-2-fluoro-4-(trifluoro- metbyl)cinnamaldehyde to obtain the
title compound, a major product as an oil in a yield of 66%.
[0115] Specific rotation [.alpha.].sub.D.sup.25 -72.degree.
(c=0.63, CHCl.sub.3)
[0116] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.20 (3H, d,
J=7.0 Hz), 3.34 (1H, q, J=7.0 Hz), 3.43 (1H, tt, J=11.3, 4.6 Hz),
3.65 (1H, t, J=11.3 Hz), 3.68 (1H, t, J=11.3 Hz), 4.34 (1H, m),
4.46 (1H, m), 4.83 (1H, d, J=14.0 Hz), 5.04 (d, J=14.0 Hz), 5.04
(1H, d, J=1.1 Hz), 5.15 (1H, d, J=4.2 Hz), 6.36 (1H, dd, J=16.3,
4.2 Hz), 6.7-6.8 (2H, m), 6.97 (1H, d, J=16.0 Hz), 7.3-7.45 (3H,
m), 7.58 (1H, t, J=7.6 Hz), 7.79 (2H, s).
EXAMPLE 9
(2R,3R)-2-(2,4-Difluorophenyl)-3-[[trans-2-[(E)-2-[4-(methylsulfonyl)pheny-
l]vinyl]-1,3-dioxan-5-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol
[0117] 211
[0118] Reaction and treatment were carried out in the same mazmer
as in Example 4 using
(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl-
)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol and
trans-4-(methylsulfonyl)cin- namaldehyde to obtain the title
compound, a major product as an oil in a yield of 58%.
[0119] NMR spectrum (60 MHz, CDCl.sub.3+D.sub.2O) .delta. ppm: 1.20
(3H, d, J=7 Hz), 3.00 (3H, s), 3.33 (1H, q, J=7 Hz), 3.5-4.0 (3H,
m), 4.2-4.8 (2H, m), 4.80 (1H, d, J=14 Hz), 5.08 (1H, d, J=14 Hz),
5.15 (1H, d, J=4 Hz), 6.30 (1H, dd, J=17, 4 Hz), 6.90 (1H, d, J=17
Hz), 6.55-7.0 (2H, m), 7.2-7.6 (1H, m), 7.58 (2H, d, J=8 Hz), 7.80
(2H, s), 7.94 (2H, d, J=8 Hz).
EXAMPLE 10
(2R,3R)-2-(2,4-Difluorophenyl)-3-[[trans-2-[(E)-2-(4-nitrophenyl)vinyl]-1,-
3-dioxan-5-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol
[0120] 212
[0121] Reaction and treatment were carried out in the same manner
as in Example 4 using
(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl-
)thio]-1-(1H-1,2,4-triazol-5-yl)-2-butanol and
trans-4-nitrocinnamaldehyde to obtain the title compound, a major
product as an oil in a yield of 40%.
[0122] Specific rotation [.alpha.].sub.D.sup.25 -64.1.degree.
(c=2.43, CHCl.sub.3)
[0123] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.19 (3H, d,
J=7.3 Hz), 3.35 (1H, q, J=7.3 Hz), 3.44 (1H, tt, J=11.2, 4.6 Hz),
3.66 (1H, t, J=11.2 Hz), 3.68 (1H, t, J=11.2 Hz), 4.34 (1H, m),
4.46 (1H, m), 4.83 (1H, d, J=13.9 Hz), 5.04 (1H, d, J=13.9 Hz),
5.04 (1H, s), 5.16 (1H, d, J=4.0 Hz), 6.32 (1H, dd, J=16.5, 4.0
Hz), 6.7-6.8 (2H, m), 6.87 (1H, d, J=16.5 Hz), 7.36 (1H, m), 7.53
(2H, d, J=8.6 Hz), 7.79 (1H s), 7.80 (1H, s), 8.19 (2H, d, J=8.6
Hz).
[0124] This compound was mixed with 1 equivalent of oxalic acid in
a mixed solvent of ethyl acetate-hexane to obtain an oxalic acid
salt crystal having a melting point of 103 to 105.degree. C.
EXAMPLE 11
(2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[trans-2-[(E)--
2-[4-(trifluoromethoxy)phenyl]vinyl]-1,3-dioxan-5-yl]thio]-2-butanol
[0125] 213
[0126] Reaction and treatment were carried out in the same masner
as in Example 4 using
(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl-
)thio]-1-(1H-1,2,4-triazol-5-yl)-2-butanol and
trans-4-(trifluoromethoxy)c- innamaldehyde as described in
Reference example 33 to obtain the title compound, a major product
as an oil in a yield of 43%.
[0127] Specific rotation [.alpha.].sub.D.sup.25 -77.degree.
(c=0.52, CHCl.sub.3)
[0128] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.20 (3H, d,
J=7.3 Hz), 3.34 (1H, q, J=2.3 Hz), 3.42 (1H, tt, J=11.2, 4.6 Hz),
3.65 (1H, t, J=11.2 Hz), 3.67 (1H, t, J=11.2 Hz), 4.32 (1H, ddd,
J=11.2, 4.6, 2.0 Hz), 4.45 (1H, ddd, J=11.2, 4.6, 2.0 Hz), 4.83
(1H, d, J=14.5 Hz), 5.01 (1H, s), 5.03 (1H, d, J=14.5 Hz), 5.12
(1H, d, J=4.0 Hz), 6.15 (1H, dd, J=16.5, 4.0 Hz), 6.7-6.8 (2H, m),
6.79 (1H, d, J=16.5 Hz), 7.17 (2H, d, J=8.6 Hz), 7.3-7.45 (1H, m),
7.42 (2H, d, J=8.6 Hz), 7.79 (2H, s).
EXAMPLE 12
(2R,3R)
-3-[[Trans-2-[(E)-2-(4-cyanophenyl)vinyl]-1,3-dioxan-5-yl]thio]-2--
(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol
[0129] 214
[0130] Reaction and treatment were carried out in the same manner
as in Example 4 using
(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl-
)thio]-1-(1H-1,2,4-triazol-5-yl)-2-butanol and
trans-4-cyanocinnamaldehyde [Mol. Cryst. Liq. Cryst. 123 257
(1985)] to obtain the title compound, a major product as an oil in
a yield of 66%.
[0131] Specific rotation [.alpha.].sub.D.sup.25 -78.degree.
(c=0.52, CHCl.sub.3)
[0132] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.20 (3H, d,
J=7.0 Hz), 3.34 (1H, br q, J=7.0 Hz), 3.43 (1H, tt, J=11.3, 4.8
Hz), 3.65 (1H, t, J=11.3 Hz), 3.67 (1H, t, J=11.3 Hz), 4.33 (1H,
m), 4.46 (1H, m), 4.83 (1H, d, J=14.2 Hz), 5.03 (1H, d, J=1.2 Hz),
5.04 (1H, d, J=14.2 Hz), 5.14 (1H, d, J=4.1 Hz), 6.28 (1H, dd,
J=16.1, 4.1 Hz), 6.7-6.8 (2H, m), 6.82 (1H, d, J=16.1 Hz), 7.36
(1H, m), 7.49 (2H, d, J=8.3 Hz), 7.62 (2H, d, J=8.3 Hz), 7.79 (2H,
s).
[0133] This compound was mixed with 1 equivalent of oxalic acid in
a mixed solvent of ethyl acetate-hexane to obtain an oxalic acid
salt crystal having a melting point of 164 to 165.degree. C.
EXAMPLE 13
(2R,3R)-2-(2,4-Difluorophenyl)-3-[[trans-2-[(E)-2-methyl-2-[4-(trifluorome-
thyl)phenyl]vinyl]-1,3-dioxan-5-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butan-
ol
[0134] 215
[0135] Reaction and treatment were carried out in the same manner
as in Example 4 using
(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl-
)thio]-1-(1H-1,2,4-triazol-l-yl)-2-butanol and
trans-.beta.-methyl-4-(trif- luoromethyl)cinnamaldehyde to obtain
the desired title compound, a major product as an oil in a yield of
73%.
[0136] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.20 (3H, d,
J=7.1 Hz), 2.16 (3H, s), 3.36 (1H, q, J=7.1 Hz), 3.41 (1H, tt,
J=11.3, 4.6 Hz), 3.66 (1H, t, J=11.3 Hz), 3.68 (1H, t, J=11.3 Hz),
4.32 (1H, m), 4.44 (1H, m), 4.83 (1H, d, J=13.9 Hz), 5.03 (1H, s),
5.04 (1H, d, J=13.9 Hz), 5.33 (1H, d, J=6.0 Hz), 5.83 (1H, br d,
J=6.0 Hz), 6.7-6.8 (2H, m), 7.3-7.45 (1H, m) , 7.51 (2H, d, J=8.3
Hz), 7.59 (2H, d, J=8.3 Hz), 7.79 (2H, s)
EXAMPLE 14
(2R,3R)-3-[[Trans-2-[(E)-2-(5-chloro-2-thienyl)vinyl]-1,3-dioxan-5-yl]thio-
]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol
[0137] 216
[0138] Reaction and treatment were carried out in the same manner
as in Example 4 using
(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl-
)thio]-1-(1H-1,2,4-triazol-5-yl)-2-butanol and
trans-.beta.-(5-cbloro-2-th- ienyl)acrolein [Chem. Abst. 51 1284 h
(1941)] to obtain the title compound as an oil in a yield of
50%.
[0139] Specific rotation [.alpha.].sub.D.sup.25 -75.7.degree.
(c=0.56, CHCl.sub.3)
[0140] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.19 (3H, d,
J=7.3 Hz), 3.33 (1H, q, J=7.3 Hz), 3.40 (1H, tt, J=11.2, 4.6 Hz),
3.62 (1H, t, J=11.2 Hz), 3.64 (1H, t, J=11.2 Hz), 4.36 (1H, m),
4.42 (1H, m), 4.82 (1H, d, J=13.8 Hz), 5.02 (1H, br s), 5.03 (1H,
d, J=13.8 Hz), 5.06 (1H, d, J=4.6 Hz), 5.88 (1H, dd, J=15.8, 4.6
Hz), 6.7-6.85 (3H, m), 6.78 (2H, s), 7.36 (1H, m), 7.87 (2H,
s).
[0141] This compound was mixed with 1 equivalent of oxalic acid in
a mixed solvent of ethyl acetate-hexane to obtain an oxalic acid
salt crystal having a melting point of 53 to 57.degree. C.
EXAMPLE 15
(2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[trans-2-[(1E,-
3E)-4-[4-(trifluoromethyl)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-
-2-butanol
[0142] 217
[0143] Reaction and treatment were carried out in the same manner
as in Example 4 using
(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl-
)thio]-1-(1H-1,2,4-triazol-5-yl)-2-butanol and
(2E,4E)-5-[4-(trifluorometb- yl)phenyl]-2,4-pentadienal as
described in Reference example 25 to obtain the title compound, a
major product as an oil in a yield of 67%.
[0144] Specific rotation [.alpha.].sub.D.sup.25 -69.8.degree.
(c=1.00, CHCl.sub.3)
[0145] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.19 (3H, d,
J=7.3 Hz), 3.33 (1H, q, J=7.3 Hz), 3.40 (1H, tt, J=11.2, 4.6 Hz),
3.62 (1H, t, J=11.2 Hz), 3.64 (1H, t, J=11.2 Hz), 4.30 (1H, m),
4.42 (1H, m), 4.82 (1H, d, J=13.9 Hz), 5.01 (1H, s), 5.03 (1H, d,
J=13.9 Hz), 5.06 (1H, d, J=4.6 Hz), 5.84 (1H, dd, J=15.2, 4.6 Hz),
6.60 (1H, dd, J=15.2, 10.6 Hz), 6.73 (1H, d, J=15.8 Hz), 6.7-6.8
(2H, m), 6.85 (1H, dd, J=15.8, 10.6 Hz), 7.3-7.45 (1H, m), 7.49
(2H, d, J=8.6 Hz), 7.56 (2H, d, J=8.6 Hz), 7.78 (2H, s).
EXAMPLE 16
(2R,3R)-2-(2,4-Difluorophenyl)-3-[[trans-2-[(1E,3E)-4-[4-(2,2,3,3-tetraflu-
oropropoxy)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-1-(1H-1,2,4-tr-
iazol-1-yl)-2-butanol
[0146] 218
[0147] Reaction and treatment were carried out in the same manner
as in Example 4 using
(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl-
)thio]-1-(1H-1,2,4-triazol-5-yl)-2-butanol and
(2E,4E)-5-[4-(2,2,3,3-tetra- fluoropropoxy)phenyl]-2,4-pentadienal
as described in Reference example 32 to obtain the title compound
having a melting point of 75 to 85.degree. C. (crystallization from
a mixed solvent of hexane-ether), a major product as a powder in a
yield of 60%.
[0148] Specific rotation [.alpha.].sub.D.sup.25 -69.degree.
(c=0.56, CHCl.sub.3)
[0149] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.18 (3H, d,
J=7.0 Hz), 3.33 (1H, q, J=7.0 Hz), 3.39 (1H, tt, J=11.3, 4.8 Hz),
3.62 (1H, t, J=11.3 Hz), 3.64 (1H, t, J=11.3 Hz), 4.30 (1H, m),
4.35 (2H, br t, J=11.8 Hz), 4.41 (1H, m), 4.82 (1H, d, J=14.1 Hz),
4.99 (1H, d, J=1.6 Hz), 5.03 (1H, d, J=14.1 Hz), 5.04 (13, d, J=4.6
Hz), 5.75 (1H, dd, J=15.7, 4.6 Hz), 6.06 (1H, tt, J=53.0, 5.1 Hz),
6.56 (1H, dd, J=15.7, 10.2 Hz), 6.57 (1H, d, J=15.0 Hz), 6.68 (1H,
dd, J=15.0, 10.2 Hz), 6.7-6.8 (2H, m), 6.88 (2H, d, J=8.7 Hz),
7.3-7.4 (1H, m), 7.37 (2H, d, J=8.7 Hz), 7.79 (2H, s).
EXAMPLE 17
(2R,3R)-3-[[Trans-2-[(1E,3E)
-4-(6-chloro-3-pyridyl)-1,3-butadien-1-yl]-1,-
3-dioxan-5-yl]thio]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-but-
anol
[0150] 219
[0151] Reaction and treatment were carried out in the same manner
as in Example 4 using
(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dibydroxy-2-propyl-
)thio]-1-(1H-1,2,4-triazol-5-yl)-2-butanol and
(2E,4E)-5-(6-chloro-3-pyrid- yl)-2,4-pentadienal as described in
Reference example 38 to obtain the title compound having a melting
point of 88 to 90.degree. C., a major product as a crystalline
solid in a yield of 69%.
[0152] Specific rotation [.alpha.]hd D.sup.25 -74.degree. (c=0.59,
CHCl.sub.3)
[0153] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.19 (3H, d,
J=7.1 Hz), 3.33 (1H, q, J=7.1 Hz), 3.40 (1H, tt, J=11.3, 4.7 Hz),
3.62 (1H, t, J=11.3 Hz), 3.64 (1H, t, J=11.3 Hz), 4.30 (1H, m),
4.42 (1H, m), 4.82 (1H, d, J=14.3 Hz), 5.00 (1H, s) , 5.03 (1H, d,
J=14.3 Hz) , 5.05 (1H, d, J=4.2 Hz), 5.84 (1H, dd, J=15.1, 4.2 Hz),
6.56 (1H, d, J=15.5 Hz), 6.58 (1H, dd, J=15.1, 10.5 Hz), 6.7-6.8
(2H, m), 6.80 (1H, dd, J=15.5, 10.5 Hz), 7.28 (1H, d, J=8.3 Hz),
7.3-7.4 (1H, m), 7.70 (1H, dd, J=8.3, 2.5 Hz), 7.79 (2H, s), 8.37
(1H, d, J=2.5 Hz).
EXAMPLE 18
(2R,3R)-2-(2,4-Difluorophenyl)-3-[[trans-2-[(1E,3Z)-4-(4-chlorophenyl)-5,5-
,5-trifluoro-1,3-pentadien-1-yl]-1,3-dioxan-5-yl]thio]-1-(1H-1,2,4-triazol-
-1-yl)-2-butanol
[0154] 220
[0155] Reaction and treatment were carried out in the same manner
as in Example 4 using
(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl-
)thio]-1-(1H-1,2,4-triazol-5-yl)-2-butanol and (2E,4Z)
-5(4-chlorophenyl)-6,6,6-trifluoro-2,4-hexadienal as described in
Reference example 52 to obtain the title compound, a major product
as an oil in a yield of 31%.
[0156] Specific rotation [.alpha.].sub.D.sup.25 -59.4.degree.
(c=0.90, CHCl.sub.3)
[0157] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.19 (3H, d,
J=7.3 Hz), 3.33 (1H, br q, J=7.3 Hz), 3.40 (1H, tt, J=11.2, 4.6
Hz), 3.61 (1H, t, J=11.2 Hz), 3.64 (1H, t, J=11.2 Hz) , 4.31 (1H,
m), 4.43 (1H, m), 4.82 (1H, d, J=13.9 Hz), 5.02 (1H, s), 5.03 (1H,
d, J=13.9 Hz), 5.09 (1H, d, J=4.6 Hz), 5.96 (1H, dd, J=15.2, 4.6
Hz), 6.50 (1H, d, J=11.9 Hz), 6.7-6.8 (2H, m), 6.9-7.1 (1H, m),
7.25-7.4 (5H, m), 7.79 (2H, s).
EXAMPLE 19
(2R,3R)-2-(2,4-Difluorophenyl)-3-[[trans-2-[(1E,3E)-2-methyl-4-[4-(trifluo-
romethyl)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-1-(1H-1,2,4-tria-
zol-1-yl)-2-butanol
[0158] 221
[0159] Reaction and treatment were carried out in the same manner
as in Example 4 using
(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl-
)thio]-1-(1H-1,2,4-triazol-5-yl)-2-butanol and
(2E,4E)-3-methyl-5-[4-(trif- luoromethyl)phenyl]-2,4-pentadienal as
described in Reference example 10 to obtain the title compound, a
major product as an oil in a yield of 70%.
[0160] Specific rotation [.alpha.].sub.D.sup.25 -68.degree.
(c=0.50, CHCl.sub.3)
[0161] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.27 (3H, d,
J=7.1 Hz), 1.99 (3H, s), 3.34 (1H, q, J=7.1 Hz), 3.39 (1H, tt,
J=11.3, 4.8 Hz), 3.64 (1H, t, J=11.3 Hz), 3.66 (1H, t, J=11.3 Hz),
4.30 (1H, m), 4.41 (1H, m), 4.83 (1H, d, J=14.1 Hz), 5.01 (1H, s),
5.04 (1H, d, J=14.1 Hz), 5.32 (1H, d, J=6.2 Hz), 5.66 (1H, d, J=6.2
Hz), 6.66 (1H, d, J=16.1 Hz), 6.7-6.8 (2H, m), 6.86 (1H, d, J=16.1
Hz), 7.3-7.4 (1H, m), 7.51 (2H, d, J=8.4 Hz), 7.57 (2H, d, J=8.4
Hz), 7.78 (2H, s).
EXAMPLE 20
(2R,3R)-2-(2,4-Difluorophenyl)-3-[[trans-2-[(1E,3E)-3-methyl-4-[4-(trifluo-
romethyl)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-1-(1H-1,2,4-tria-
zol-1-yl)-2-butanol
[0162] 222
[0163] Reaction and treatment were carried out in the same manner
as in Example 4 using
(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl-
)thio]-1-(1H-1,2,4-triazol-5-yl)-2-butanol and
(2E,4E)-4-methyl-5-[4-(trif- luoromethyl)phenyl]-2,4-pentadienal to
obtain the title compound, a major product as an oil in a yield of
69%.
[0164] Specific rotation [.alpha.].sub.D.sup.25 -63.4.degree.
(c=1.07, CHCl.sub.3)
[0165] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.19 (3H, d,
J=7.0 Hz), 2.00 (3H, s), 3.33 (1H, q, J=7.0 Hz), 3.41 (1H, tt,
J=11.2, 4.6 Hz), 3.64 (1H, t, J=11.2 Hz), 3.66 (1H, t, J=11.2 Hz),
4.31 (1H, m), 4.43 (1H, m), 4.83 (1H, d, J=14.2 Hz), 5.01 (1H, s),
5.04 (1H, d, J=14.2 Hz), 5.09 (1H, d, J=4.6 Hz), 5.81 (1H, dd,
J=16.0, 4.6 Hz), 6.60 (1H, s), 6.63 (1H, d, J=16.0 Hz), 6.7-6.8
(2H, m), 7.3-7.4 (1H, m), 7.38 (2H, d, J=8.2 Hz), 7.59 (2H, d,
J=8.2 Hz), 7.79 (2H, s).
EXAMPLE 21
(2R,3R)-2-(2,4-Difluorophenyl)-3-[[1-[(E)-4-(trifluoromethoxy)cinnamoyl]pi-
peridin-4-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol
[0166] 223
[0167] [Process A]
[0168] To a mixture of 150 mg (0.340 mmol) of
(2R,3R)-(2,4-difluorophenyl)-
-3-(1H-1,2,4-triazol-1-yl)-3-[(piperidin-4-yl)thio]-2-butanol
dihydrochloride as described in Reference example 14 and 3 ml of
dichloromethane were added 142 .mu.l (1.02 mmol) of triethylamine
at 0.degree. C. under nitrogen atmosphere and, after 5 minutes, 128
mg (0.510 mmol) of (E)-4-(trifluoromethoxy)cinnamoyl chloride. The
mixture was stirred at the same temperature for 30 minutes and the
solvent was distilled off, and then ethyl acetate was added to the
thus obtained residue, followed by washing of the mixture with an
aqueous NaCl solution. The solvent was distilled off and the
residue was subjected to silica gel column chromatography, followed
by elution with ethyl acetate to obtain 160 mg (yield: 81%) of the
title compound as a colorless foam.
[0169] NMR spectru (270 MHz, CDCl.sub.3) .delta. ppm: 1.19 (3H, d,
J=7.0 Hz), 1.6-1.8 (2H, m), 2.0-2.1 (2H, m), 3.0-3.2 (2H, m), 3.35
(1H, q, J=7.0 Hz), 3.2-3.4 (1H, m), 4.0-4.1 (1H, m), 4.2-4.3 (1H,
m), 4.83 (1H, s), 4.83 (1H, d, J=14.0 Hz), 5.09 (1H, d, J=14.0 Hz),
6.7-6.8 (2H, m), 6.87 (1H, d, J=15.5 Hz), 7.22 (2H, d, J=8.5 Hz),
7.3-7.4 (1H, m), 7.55 (2H, d, J=8.5 Hz), 7.65 (1H, d, J=15.5 Hz),
7.78 (1H, s), 7.82 (1H, s). IR spectrum
.nu..sub.max.sup.KBrcm.sup.-1: 3421, 1695, 1686, 1617, 1591. Mass
spectrum m/e: 582, 563, 522, 500, 427, 359, 299, 258, 215, 187,
144, 101, 82.
[0170] [Process B]
[0171] In 4 ml of dimethylformamide were dissolved 327 mg (0.875
mmol) of
4-(acetylthio)-1-[(E)-4-(trifluoromethoxy)cinnamoyl]piperidine as
described in Reference example 16 and 200 mg (0.796 mmol) of
(2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]-
oxirane, and 129 .mu.l (0.613 mmol) of a 28% sodium
methoxide-methanol solution were added to the mixture under
nitrogen atmosphere, followed by stirring of the resulting mixture
at 50.degree. C. for 3 hours. After cooling, ethyl acetate was
added to the reaction mixture to dilute it and washed with water
and then a saturated aqueous NaCl solution.
[0172] The oil obtained by evaporation of the solvent was subjected
to silica gel column chromatography and eluted with ethyl acetate
to obtain 275 mg (yield: 59%) as a colorless foam. The present
compound was identified as the compound obtained according to the
[Process A] by means of each spectrum of NMR, IR and MS.
EXAMPLE 22
(2R,3R)-2-(2,4-Difluorophenyl)-3-[[1-((E)
-4-methylcinnamoyl)piperidin-4-y-
l]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol
[0173] 224
[0174] A colorless foam obtained from (E)-4-methylcinnamoyl
chloride (Can. J. Chem. 45 1001 (1967)] according to [Process A] of
Example 21.
[0175] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.19 (3H, d,
J=7.0 Hz), 1.6-1.8 (2H, m), 2.0-2.2 (2H, m), 2.37 (3H, s), 3.0-3.2
(2H, m), 3.2-3.4 (1H, m), 3.35 (1H, q, J=7.0 Hz), 4.0-4.2 (1H, m),
4.4-4.6 (1H, m), 4.83 (1H, d, J=13.9 Hz), 4.84 (1H, s), 5.09 (1H,
d, J=13.9 Hz), 6.7-6.8 (2H, m), 6.85 (1H, d, J=15.5 Hz), 7.18 (2H,
d, J=8.3 Hz), 7.3-7.4 (1H, m), 7.43 (2H, d, J=8.3 Hz), 7.65 (1H, d,
J=15.5 Hz), 7.77 (1H, s), 7.82 (1H, s). IR spectrum
.nu..sub.max.sup.KBrcm.sup.-1: 3333, 1645, 1599. Mass spectrum m/e:
512, 510, 452, 430, 425, 367, 357, 289, 229, 224, 188, 145, 117,
82.
EXAMPLE 23
(2R,3R)-2-(2,4-Difluorophenyl)-3-[[1-((E)-4-nitrocinnamoyl)piperidin-4-yl]-
thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol
[0176] 225
[0177] A slightly yellow foam obtained from (E)-4-nitrocinnamoyl
chloride according to [Process A] of Example 21.
[0178] NMR spectrum (270 Mz, CDCl.sub.3) .delta. ppm: 1.26 (3H, d,
J=6.6 Hz), 1.6-1.9 (2H, m), 2.1-2.3 (2H, m), 3.1-3.3 (2H, m),
3.3-3.5 (1H, m), 3.42 (1H, q, J=6.6 Hz), 4.0-4.2 (1H, m), 4.4-4.6
(1H, m), 4.89 (1H, d, J=13.9 Hz), 4.92 (1H, s), 5.15 (1H, d, J=13.9
Hz), 6.7-6.9 (2H, m), 7.10 (1H, d, J=15.5 Hz), 7.4-7.5 (1H, m),
7.73 (2H, d, J=8.9 Hz), 7.75 (1H, d, J=15.5 Hz), 7.86 (2H, d, J=8.9
Hz), 8.29 (1H, s), 8.32 (1H, s). IR spectrum
.nu..sub.max.sup.KBrcm.sup.-1: 3361, 1649, 1612, 1518, 1345. Mass
spectrum m/e: 544, 525, 513, 483, 461, 388, 365, 284, 260, 224,
219, 176, 144, 130, 82.
EXAMPLE 24
(2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[1-[(2E,4E)-5--
[4-(trifluoromethoxy)phenyl]-2,4-pentadienoyl]piperidin-4-yl]thio]-2-butan-
ol
[0179] 226
[0180] A colorless foam obtained from
(2E,4E)-5-[4-(trifluoromethoxy)pheny- l]-2,4-pentadienoyl chloride
according to [Process A] of Example 21.
[0181] NMR spectrum (270MHz, CDCl.sub.3) .delta. ppm: 1.19 (3H, d,
J=6.6 Hz), 1.5-1.8 (2H, m), 2.0-2.2 (2H, m), 3.0-3.3 (3H, m), 3.34
(1H, q, J=6.6 Hz), 3.9-4.1 (1H, m), 4.3-4.5 (1H, m), 4.83 (1H, d,
J=13.9 Hz), 4.82 (1H, s), 5.08 (1H, d, J=13.9 Hz), 6.50 (1H, d,
J=14.5 Hz), 6.7-6.8 (2H, m), 6.8-6.9 (2H, m), 7.20 (2H, d, J=8.9
Hz), 7.3-7.5 (2H, m), 7.47 (2H, d, J=8.9 Hz), 7.78 (1H, s), 7.82
(1H, s). IR spectrum .nu..sub.max.sup.KBrcm.sup.-1: 3395, 1639,
1616, 1596. Mass spectrum m/e: 608, 589, 548, 526, 453, 433, 385,
325, 241, 224, 213, 144, 127, 82.
EXAMPLE 25
(2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[1-[(E)-3-(pyr-
idin-4-yl)-acryloyl]01059 piperidin-4-yl]thio]-2-butanol
[0182] 227
[0183] A colorless foam obtained from
4-acetylthio-1-[(E)-3-(pyridin-4-yl)- -acryloyl]piperidine
according to [Process B] of Example 21.
[0184] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.20 (3H, d,
J=6.6 Hz), 1.6-1.8 (2H, m), 2.0-2.2 (2H, m), 3.0-3.2 (2H, m), 3.35
(1H, q, J=6.6 Hz), 3.2-3.4 (1H, m), 3.9-4.1 (1H, m), 4.3-4.5 (1H,
m), 4.83 (1H, d, J=14.5 Hz), 4.86 (1H, s), 5.09 (1H, d, J=14.5 Hz),
6.7-6.8 (2H, m), 7.06 (1H, d, J=15.2 Hz), 7.3-7.4 (1H, m), 7.37
(2H, d, J=5.9 Hz), 7.57 (1H, d, J=15.2 Hz), 7.78 (1H, s), 7.81 (1H,
s), 8.64 (2H, d, J=5.9 Hz). IR spectrum
.nu..sub.max.sup.KBrcm.sup.-1: 3420, 1651, 1615, 1598. Mass
spectrum m/e: 499, 439, 417, 410, 365, 344, 307, 275, 247, 216,
144, 132, 104, 82.
EXAMPLE 16
(2R,3R)-2-(2,4-Difluorophenyl)-3-[[1-(E)-4-(trifluoromethoxy)cinnamoyl]aze-
tidin-3-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol
[0185] 228
[0186] A slightly yellow foam obtained from
(2R,3R)-2-(2,4-difluorophenyl)-
-1-(1H-1,2,4-triazol-1-yl)-3-[(azetidin-3-yl]thio]-2-butanol
dihydrochloride according to [Process A] of Example 21.
[0187] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.17 (3H, d,
J=7.1 Hz), 3.32 (1H, q, J=7.1 Hz), 4.0-4.3 (3H, m), 4.5-4.6 (1H,
m), 4.6-4.7 (1H, m)), 4.86 (1H, d, J=14.2 Hz), 5.05 (1H, d, J=14.2
Hz), 5.09 (1H, s), 6.43 (1H, d, J=15.7 Hz), 6.7-6.8 (2H, m), 7.22
(2H, d, J=8.2 Hz), 7.3-7.4 (1H, m), 7.56 (2H, d, J=8.2 Hz), 7.65
(1H, d, J=15.7 Hz), 7.79 (1H, s), 7.81 (1H, s). IR spectrum
.nu..sub.max.sup.KBrcm.sup.-1: 3376, 1656. Mass spectrum m/e: 554,
535, 472, 384, 331, 271, 224, 215, 187, 127, 87.
EXAMPLE 27
(2R,3R)-2-(2,4-Difluorophenyl)-3-[[(trans-2-[(1E,3E)
-4-(2,4-difluorophenyl)-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-1-(1H-1,-
2,4-triazol-1-yl)-2-butanol
[0188] 229
[0189] Reaction was carried out in the same manner as in Example 4
using
(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2-
,4-triazol-5-yl)-2-butanol and
(2E,4E)-5-(2,4-difluorophenyl)-2,4-pentadie- nal to obtain the
title compound, a major product as an oil in a yield of 61%.
[0190] Specific rotation [.alpha.].sub.D.sup.25 -79.1.degree.
(c=1.04, CHCl.sub.3)
[0191] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.18 (3H, d,
J=7.0 Hz), 3.33 (1H, q, J=7.0 Hz), 3.39 (1H, tt, J=11.3, 4.6 Hz),
3.62 (1H, t, J=11.3 Hz), 3.64 (1H, t, J=11.3 Hz), 4.30 (1H, m),
4.41 (1H, m), 4.82 (1H, d, J=14.0 Hz), 5.00 (1H, s), 5.03 (1H, d,
J=14.0 Hz), 5.05 (1H, d, J=4.6 Hz), 5.79 (1H, dd, J=15.2, 4.6 Hz),
6.58 (1H, dd, J=15.2, 9.5 Hz), 6.65-6.9 (6H, m), 7.3-7.5 (2H, m),
7.79 (2H, s).
EXAMPLE 28
(2R,3R)-2-(2,4-Difluoropheoyl)-3-[[trans-2-[(1E,3E)
-4-[6-(2,2,3,3-tetrafluoropropoxy)-3-pyridyl]-1,3-butadien-1-yl]-1,3-diox-
an-5-yl]thio]-1-(1H-1,2,4-triazol-5-yl)-2-butanol
[0192] 230
[0193] In 11 ml of methylene chloride were dissolved 404 mg (1.12
mmol) of
(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2-
,4-triazol-1-yl)-2-butanol and 501 mg (1.73 mmol) of
(2E,4E)-5-[6-(2,2,3,3-tetrafluoropropoxy)-3-pyridyl]-2,4-pentadienal
as described in Reference example 37, and 320 mg (1.68 mmol) of
p-toluenesulfonic acid monohydrate and 4 g of molecular sieves 4A
were added to the solution, followed by stirring of the resulting
mixture at room temperature for 1 hour. The reaction mixture was
poured into 20 ml of a 3% aqueous sodium hydrogencarbonate solution
under ice-cooling and the mixture was stirred for 5 minutes. Then,
the molecular sieves was removed by filtration and the organic
layer was collected by fractions, followed by drying and
evaporation of the solvent under reduced pressure. 908 mg of the
thus obtained oil were subjected to column chromatography using 19
g of silica gel and eluted with a mixed solvent of hexane-ethyl
acetate (1:1) to obtain 448 mg (yield: 63%) of the desired title
compound as an oil.
[0194] Specific rotation [.alpha.].sub.D.sup.25 -58.6.degree.
(c=0.52, CHCl.sub.3)
[0195] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.19 (3H,
J=7.0 Hz), 3.33 (1H, q, J=7.0 Hz), 3.39 (1H, tt, J=11.2, 4.8 Hz),
3.62 (1H, t, J=11.2 Hz), 3.64 (1H, t, J=11.2 Hz), 4.30 (1H, ddd,
J=11.2, 4.7, 2.1 Hz), 4.42 (1H, ddd, J=11.2, 4.7, 2.1 Hz), 4.74
(2H, brt, J=12.8 Hz), 4.82 (1H, d, J=13.9 Hz), 5.01 (1H, s), 5.03
(1H, d, J=13.9 Hz), 5.05 (1H, d, J=4.5 Hz), 5.78 (1H, d, J=15.5,
4.5 Hz), 6.01 (1H, tt, J=53.1, 4.6 Hz), 6.51-6.62 (2H, m),
6.65-6.78 (3H, m), 6.81 (1H, d, J=8.6 Hz), 7.35 (1H, m), 7.74 (1H,
dd, J=8.6, 2.3 Hz), 7.79 (2H, s), 8.11 (1H, d, J=2.3 Hz).
EXAMPLE 29
(2R,3R)-2-(2,4-Difluorophenyl)-3-[[trans-2-[(1E,3E)-1-methyl-4-[4-(trifluo-
romethyl)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-1-(1H-1,2,4-tria-
zol-1-yl)-2-butanol
[0196] 231
[0197] Reaction was carried out in the same manner as in Example 4
using
(2R,3R)-2-(2,4-diphenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-tri-
azol-5-yl)-2-butanol and
(2E,4E)-2-methyl-5-[4-(trifluoromethyl)phenyl]-2,- 4-pentadienal to
obtain the title compound, a major product as an oil in a yield of
31%.
[0198] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.19 (3H, d,
J=7.3 Hz), 1.94 (3H, s), 3.34 (1H, q, J=7.3 Hz), 3.39 (1H, tt,
J=11.2, 4.6 Hz), 3.36 (1H, t, J=11.2 Hz), 3.65 (1H, t, J=11.2 Hz),
4.33 (1H, m), 4.44 (1H, m), 4.83 (1H, d, J=13.9 Hz), 4.89 (1H, s),
5.02 (1H, s), 5.04 (1H, d, J=13.9 Hz), 6.41 (1H, d, J=11.2 Hz),
6.62 (1H, d, J=15.8 Hz), 6.7-6.8 (2H, m), 7.09 (1H, dd, J=15.8,
11.2 Hz), 7.36 (1H, m), 7.50 (2H, d, J=8.6 Hz), 7.56 (2H, d, J=8.6
Hz), 7.79 (1H, s), 7.80 (1H, s).
EXAMPLE 30
(RS)
-3-Methyl-1-(1H-1,2,4-triazol-1-yl)-2-[4-(trifluoromethyl)phenyl]-3-[-
[trans-2-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]-1,3-dioxan-5-yl]thio]-2--
butanol
[0199] 232
[0200] Reaction was carried out in the same maaner as in Example 4
using
(RS)-3-[(1,3-dihydroxy-2-propyl)thio]-3-methyl-2-[4-(trifluoromethyl)phen-
yl]-1-(1H-1,2,4-triazol-1-yl)-2-butanol as described in Reference
example 55 and trans-4-(trifluoromethyl)cinnamaldehyde as described
in Reference example 22 to obtain the title compound as a colorless
foam.
[0201] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.36 (3H,
s), 1.37 (3H, s), 3.5-3.7 (3H, m), 4.2-4.3 (1H, m), 4.4-4.5 (1H,
m), 5.02 (2H, s), 5.11 (1H, d, J=4.1 Hz), 5.44 (1H, s), 6.25 (1H,
dd, J=16.2, 4.1 Hz), 6.84 (1H, d, J=16.2 Hz), 7.4-7.6 (8H, m), 7.70
(1H, s), 7.93 (1H, s). IR spectrum .nu..sub.max (KBr) cm.sup.-1:
3404, 1618, 1508, 1328. Mass spectrum m/e: 587, 568, 331, 298, 256,
201, 159, 131.
EXAMPLE 31
(RS)-3-Methyl-1-(1H-1,2,4-triazol-1-yl)-2-[4-(trifluoromethyl)phenyl]-3-[[-
trans-2-[(1E,3E)-4-[(trifluoromethyl)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-
-5-yl]thio]-2-butanol
[0202] 233
[0203] Reaction was carried out in the same mazmer as in Example 4
using
(RS)-3-[(1,3-dihydroxy-2-propyl)thio]-3-methyl-2-[4-(trifluoromethyl)phen-
yl]-1-(1H-1,2,4-triazol-1-yl)-2-butanol as described in Reference
example 55 and
(2E,4E)-5-[4-(trifluoromethyl)phenyl]-2,4-pentadienal as described
in Reference example 25 to obtain the title compound, a major
product as a colorless foam.
[0204] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.36 (3H,
s), 1.37 (3H, s), 3.4-3.7 (3H, m), 4.2-4.3 (1H, m), 4.4-4.5 (1H,
m), 5.01 (2H, s), 5.02 (1H, d, J=4.3 Hz), 5.39 (1H, s), 5.83 (1H,
dd, J=15.2, 4.3 Hz), 6.59 (1H, dd, J=15.2, 10.7 Hz), 6.63 (1H, d,
J=15.8 Hz), 6.85 (1H, dd, J=15.8, 10.7 Hz), 7.4-7.6 (8H, m), 7.73
(1H, s), 7.93 (1H, s). IR spectrum .nu..sub.max (KBr) cm.sup.-1:
3398, 1679, 1619, 1328, 1126. Mass spectrum m/e: 614, 541, 494,
478, 406, 348, 256, 211.
EXAMPLE 32
(2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[trans-2-[(1E,-
3E)-4-[4-(trifluoromethylthio)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5-yl]t-
hio]-2-butanol
[0205] 234
[0206] Reaction was carried out in the same manner as in Example 4
using
(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2-
,4-triazol-5-yl)-2-butanol and
(2E,4E)-5-[4-(trifluoromethylthio)phenyl]-2- ,4-pentadienal to
obtain the title compound, a major product as a colorless foam.
[0207] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.19 (3H, d,
J=7.1 Hz), 3.3-3.5 (2H, m), 3.62 (1H, t, J=11.4 Hz), 3.64 (1H, t,
J=11.4 Hz), 4.31 (1H, ddd, J=11.4, 4.7, 2.1 Hz), 4.42 (1H, ddd,
J=11.4, 4.7, 2.1 Hz), 4.83 (1H, d, J=14.1 Hz), 5.01 (1H, s), 5.03
(1H, d, J=14.1 Hz), 5.06 (1H, d, J=4.5 Hz), 5.83 (1H, dd, J=15.7,
4.5 Hz), 6.60 (1H, dd, J=15.7, 10.3 Hz), 6.62 (1H, d, J=15.7 Hz),
6.7-6.8 (2H, m), 6.84 (1H, dd, J=15.7, 10.3 Hz), 7.3-7.4 (1H, m),
7.44 (2H, d, J=8.3 Hz), 7.60 (2H, d, J=8.3 Hz), 7.79 (2H, s). IR
spectrum .nu..sub.max (KBr) cm.sup.-1: 3389, 1621, 1680, 1621,
1501, 1117. Mass spectrum m/e: 599, 580, 557, 530, 500, 438, 388,
376, 346, 284, 258, 224, 183.
EXAMPLE 33
(2R*, 3R*)-3-[[Trans -2
-(1E,3E)-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-- 1,3
-butadien-1-yl]-1,3 -dioxan-5-yl]thio]-1-(1H-1,
2,4-triazol-1-yl)-2-[4-(trifluoromethyl)phenyl]-2-butanol
[0208] 235
[0209] Reaction was carried out in the same mazer as in Example 1
using
(2R*,3R*)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-5-yl)-2-[4-
-(trifluoromethyl)phenyl]-2-butanol and
(2E,4E)-5-[4-(2,2,3,3-tetrafluorop- ropoxy)phenyl]-2,4-pentadienal
as described in Reference example 32 to obtain the title compound,
a major product as an oil.
[0210] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.22 (3H, d,
J=6.6 Hz), 3.16 (1H, q, J=6.6 Hz), 3.34 (1H, tt, J=11.2, 4.6 Hz),
3.58 (1H, t, J=11.2 Hz), 3.61 (1H, t, J=11.2 Hz), 4.27 (1H, m),
4.35 (2H, br t, J=11.9 Hz), 4.39 (1H, m), 4.57 (1H, d, J=13.9 Hz),
4.77 (1H, s), 5.02 (1H, d, J=4.6 Hz), 5.03 (1H, d, J=13.9 Hz), 5.72
(1H, dd, J=15.8, 4.6 Hz), 6.05 (1H, tt, J=52.8, 5.3 Hz), 6.5-6.75
(3H, m), 6.88 (2H, d, J=8.6 Hz), 7.36 (2H, d, J=8.6 Hz), 7.39 (2H,
d, J=8.6 Hz), 7.54 (2H, d, J=8.6 Hz), 7.71 (1H, s), 7.83 (1,
s).
EXAMPLE 34
(2R*,3R*)-1-(1H-1,2,4-Triazol-1-yl)-2-[4-(trifluoromethyl)phenyl]-3-[[tran-
s-2-[(1E,3E)-4-[4-(trifluoromethyl)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5
-yl]thio]-2-butanol
[0211] 236
[0212] Reaction was carried out in the same manner as in Example 1
using (2R*,3R*)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane
and
trans-5-(acetylthio)-2-[(1E,3E)-4-[4-(trifluoromethyl)phenyl]-1,3-butadie-
n-1-yl]-1,3-dioxane to obtain the title compound as an oil in a
yield of 71%.
[0213] NMR spectrum (270MHz, CDCl.sub.3) .delta. ppm: 1.22 (3H, d,
J=7.0 Hz), 3.17 (1H, q, J=7.0 Hz), 3.36 (1H, tt, J=11.3, 4.7 Hz),
3.59 (1H, t, J=11.3 Hz), 3.62 (1H, t, J=11.3 Hz), 4.27 (1H, ddd,
J=11.3, 4.7, 2.2 Hz), 4.39 (1H, ddd, J=11.3, 4.7, 2.2 Hz), 4.57
(1H, d, J=14.0 Hz), 4.80 (1H, s), 5.03 (1H, d, J=14.0 Hz), 5.05
(1H, d, J=4.5 Hz), 5.83 (1H, dd, J=15.3, 4.5 Hz), 6.59 (1H, dd,
J=15.3, 10.7 Hz), 6.64 (1H, d, J=15.3 Hz), 6.85 (1H, dd, J=15.3,
10.7 Hz), 7.39 (2H, d, J=8.4 Hz), 7.49 (2H, d, J=8.3 Hz), 7.54 (2H,
d, J=8.3 Hz), 7.57 (2H, d, J=8.4 Hz), 7.71 (1H, s), 7.83 (1H,
s).
EXAMPLE 35
(2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[trans-2-[(1E,-
3E)-4-[4-(trifluoromethylsulfinyl)phenyl]-1,3-butadien-l-yl]-1,3-dioxan-5--
yl]thio]-2-butanol
[0214] 237
[0215] Reaction was carried out in the same manner as in Example 4
using
(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2-
,4-triazol-5-yl)-2-butanol and
(2E,4E)-5-[4-(trifluoromethylsulfinyl)pheny- l]-2,4-pentadienal to
obtain the title compound, a major product as a colorless foam.
[0216] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.19 (3H, d,
J=7.0 Hz), 3.3-3.5 (2H, m), 3.62 (1H, t, J=11.3 Hz), 3.64 (1H, t,
J=11.3 Hz), 4.30 (1H, ddd, J=11.3, 4.8, 2.3 Hz), 4.42 (1H, ddd,
J=11.3, 4.8, 2.3 Hz), 4.83 (1H, d, J=14.1 Hz), 5.01 (1H, s), 5.03
(1H, d, J=14.1 Hz), 5.06 (1H, d, J=4.5 Hz), 5.83 (1H, dd, J=15.9,
4.5 Hz), 6.60 (1H, dd, J=15.9, 10.6 Hz), 6.62 (1H, d, J=15.9 Hz),
6.7-6.8 (2H, m), 6.84 (1H, dd, J=15.9, 10.6 Hz), 7.3-7.4 (1H, m),
7.44 (2H, d, J=8.3 Hz), 7.60 (2H, d, J=8.3 Hz), 7.79 (2H, s). Mass
spectrum m/e: 616, 600, 547, 400, 370, 342, 284, 252, 224, 183.
EXAMPLE 36
(2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[trans-4-[(1E,-
3E)-4-[4-(trifluoromethyl)phenyl]-1,3-butadien-1-yl]cyclohexyl]thio]-2-but-
anol
[0217] 238
[0218] Reaction was carried out in the same mamner as in Example 1
using
(2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol1-yl)methyl]o-
xirane and
trans-1-(acetylthio)-4-[(1E,3E)-4-[4-(trifluoromethyl)phenyl]-1-
,3-butadien-1-yl]cyclohexane as described in Reference example 43
to obtain the title compound having a melting point of 74 to
76.degree. C. in a yield of 59%.
[0219] Specific rotation [.alpha.].sub.D.sup.25 -83.degree.
(c=0.90, CHCl.sub.3)
[0220] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.1-1.6 (4H,
m), 1.17 (3H, d, J=7 Hz), 1.8-2.0 (2H, m), 2.0-2.2 (2H, m), 2.69
(1H, tt, J=12.3 Hz), 3.35 (1H, q, J=7 Hz), 4.64 (1H, s, OH), 4.83
(1H, d, J=15 Hz), 5.10 (1H, d, J=15 Hz), 5.83 (1H, dd, J=15, 7 Hz),
6.22 (1H, dd, J=15, 10 Hz), 6.48 (1H, d, J=15 Hz), 6.74 (1H, t, J=8
Hz), 6.81 (1H, dd, J=15, 10 Hz), 7.1-7.5 (2H, m), 7.45 (2H, d, J=8
Hz), 7.54 (2H, d, J=8 Hz), 7.76 (1H, s), 7.84 (1H, s). IR spectrum
.nu..sub.max (CHCl.sub.3) cm.sup.-1: 1615, 1500, 1325, 1125, 1068.
Mass spectrum m/e: 563, 544, 340, 310, 277, 224, 159, 127.
EXAMPLE 37
(2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[trans-2-[(1E,-
3E,5E)-6-[4-(trifluoromethyl)phenyl]-1,3,5-hexatrien-1-yl]-1,3-dioxan-5-yl-
]thio]-2-butanol
[0221] 239
[0222] Reaction was carried out in the same maner as in Example 4
using
(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2-
,4-triazol-1-yl)-2-butanol and
(2E,4E,6E)-7-[4-(trifluoromethyl)phenyl]-2,- 4,6-heptatrienal as
described in Reference example 28 to obtain the title compound, a
major product as an oil in a yield of 65%.
[0223] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.18 (3H, d,
J=6.6 Hz), 3.33 (1H, q, J=6.6 Hz), 3.38 (1H, tt, J=11.2, 4.6 Hz),
3.61 (1H, t, J=11.2 Hz), 3.63 (1H, t, J=11.2 Hz), 4.29 (1H, m),
4.40 (1H, m), 4.83 (1H, d, J=14.5 Hz), 5.00 (1H, s), 5.02 (1H, d,
J=14.5 Hz), 5.03 (1H, d, J=4.6 Hz), 5.74 (1H, dd, J=15.2, 4.6 Hz),
6.35-6.55 (3H, m), 6.59 (1H, d, J=15.2 Hz), 6.7-6.8 (2H, m), 6.89
(1H, dd, J=15.2, 9.9 Hz), 7.35 (1H, m), 7.48. (2H, d, J=8.6 Hz),
7.56 (2H, d, J=8.6 Hz), 7.78 (1H, s), 7.79 (1H, s).
EXAMPLE 38
(RS)-2-(2,4-Difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-3-[[trans-2-
-[(1E,r3E)-4-[4-(trifluoromethyl)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5-y-
l]thio]-2-butanol
[0224] 240
[0225] Reaction was carried out in the same manner as in Example 4
using
(RS)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-3-methyl-1-(-
1H-1,2,4-triazol-1-yl)-2-butanol and
(2E,4E)-5-[4-(trifluoromethyl)phenyl]- -2,4-pentadienal as
described in Reference example 25 to obtain the title compound, a
major product as a colorless foam.
[0226] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.36 (6H,
s), 3.5-3.6 (2H, m), 3.6-3.8 (2H, m), 4.2-4.4 (1H, m), 4.4-4.6 (1H,
m), 4.93 (1H, d, J=14.1 Hz), 5.03 (1H, d, J=4.3 Hz), 5.23 (1H, d,
J=14.1 Hz), 5.56 (1H, s), 5.84 (1H, dd, J=15.4, 4.3 Hz), 6.5-6.7
(3H, m), 6.7-6.9 (2H, m), 7.50 (2H, d, J=8.4 Hz), 7.57 (2H, d,
J=8.4 Hz), 7.6-7.7 (1H, m), 7.74 (1H, s), 8.05 (1H, s).
EXAMPLE 39
(2R,3R)
-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[trans-2-[(E)-
-4-[4-(trifluoromethyl)phenyl]-1-buten-3-yn-1-yl]-1,3-dioxan-5-yl]thio]-2--
butanol
[0227] 241
[0228] Reaction was carried out in the same manner as in Example 4
using
(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2-
,4-triazol-1-yl)-2-butanol and
(E)-5-[4-(trifluoromethyl)phemyl]-2-penten-- 4-ynal as described in
Reference example 48 to obtain the title compound, a major product
as an oil in a yield of 70%.
[0229] Specific rotation [.alpha.].sub.D.sup.25 -65.1.degree.
(c=0.97, CHCl.sub.3)
[0230] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.19 (3H, d,
J=7.0 Hz), 3.33 (1H, q, J=7.0 Hz), 3.39 (1H, tt, J=11.4, 4.9 Hz),
3.60 (1H, t, J=11.4 Hz), 3.62 (1H, t, J=11.4 Hz), 4.30 (1H, m),
4.42 (1H, m), 5.0-5.1 (2H, m), 5.04 (1H, d, J=3.2 Hz), 6.12 (1H, d,
J=16.0 Hz), 6.18 (1H, dd, J=16.0, 3.2 Hz), 6.7-6.8 (2H, m), 7.36
(1H, m), 7.54 (2H, d, J=8.5 Hz), 7.58 (2H, d, J=8.5 Hz), 7.79 (2H,
s).
EXAMPLE 40
(2R,3R)-2-(2,4-Difluorophenyl)-3-[[trang-2-phenyl-1,3-dioxan-5-yl]thio]-1--
(1H-1,2,4-triazol-1-yl)-2-butanol
[0231] 242
[0232] In 20 ml of dimethylformamide were dissolved 1.65 g (6.57
mmol) of
(2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyl]o-
xirane and 2.00 g (8.40 mmol) of
trans-4-(acetylthio)-2-phenyl-1,3-dioxane as described in Reference
example 1, and 2.5 ml (4.00 mmol) of a 1.6M sodium
methoxide-methanol solution were added to the solution under a
nitrogen atmosphere, followed by heating of the resulting mixture
with stirring at 65.degree. C. for 2 hours. After cooling, ethyl
acetate was added to the reaction mixture and the resulting mixture
was washed with a saturated aqueous NaCl solution and dried,
followed by evaporation of the solvent under reduced pressure. The
thus obtained crude product was subjected to column chromatography
using 60 g of silica gel and eluted with a mixed solvent of
benzene-ethyl acetate (5:1) to obtain 2.53 g (yield: 91%) of the
title compound as a solid. The solid was recrystallized from ethyl
acetate-hexane to obtain a pure product having a melting point of
58 to 60.degree. C.
[0233] Specific rotation [.alpha.].sub.D.sup.25 -88.degree.
(c=1.07, CHCl.sub.3)
[0234] IR spectrum .nu..sub.max (CHCl.sub.3)cm.sup.-1: 3400, 1615,
1500, 1139. NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.21
(3H, d, J=7.3 Hz), 3.36 (1H, q, J=7.3 Hz), 3.48 (1H, tt, J=11.2,
4.6 Hz), 3.75 (1H, t, J=11.2 Hz), 3.77 (1H, t, J=11.2 Hz), 4.40
(1H, ddd, J=11.2, 4.6, 2.6 Hz), 4.51 (1H, ddd, J=11.2, 4.6, 2.6
Hz), 4.84 (1H, d, J=13.9 Hz), 5.02 (1H, s), 5.05 (1H, d, J=13.9
Hz), 5.49 (1H, s), 7.7-7.8 (2H, m), 7.3-7.45 (4H, m), 7.45-7.53
(2H, m), 7.79 (2H, s).
REFERENCE EXAMPLE 1
Trans-4-(acetylthio)-2-phenyl-1,3-dioxane
[0235] 243
[0236] In 200 ml of dimethylformamide were dissolved 29.0 g (86.8
mmol) of cis-2-phenyl-4-(p-toluenesulfonyloxy)-1,3-dioxane and 17.0
g (149 mmol) of sodium thioacetate, and the solution was heated at
115 to 120.degree. C. under a nitrogen atmosphere for 1 hour. After
cooling, benzene was added to the reaction mixture and the mixture
was washed with water, followed by evaporation of the solvent. The
thus obtained brown residue was subjected to column chromatography
using silica gel and the fractions eluted with a mixed solvent of
benzene-hexane (2:1) were collected, followed by recrystallization
from a mixed solvent of benzene-hexane to obtain 8.99 g (yield:
43%) of the title compound having a melting point of 95 to
96.degree. C.
[0237] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 2.37 (3H,
s), 3.79 (2H, t, J=11.2 Hz), 4.03 (1H, tt, J=11.2, 4.6 Hz), 4.31
(2H, dd, J=11.2, 4.6 Hz), 5.47 (1H, s), 7.35-7.5 (5H, m). IR
spectrum .nu..sub.max (CHCl.sub.3) cm.sup.-1: 1690, 1383, 1146,
1084. Mass spectrum m/e: 238 (M.sup.+), 237, 195, 162(100%), 149,
116, 107,
REFERENCE EXAMPLE 2
(2R,3R)-2-(2,4-Difluorophenyl)-3-[(1,3-dihydroxy-2-propyl]thio]-1-(1H-1,2,-
4-triazol-1-yl)-2-butanol
[0238] 244
[0239] In 3.5 ml of methanol were dissolved 253 mg of
(2R,3R)-2-(2,4-difluorophenyl)-3-[[trans-2-phenyl-1,3-dioxan-5-yl]thio]-1-
-(1H-1,2,4-triazol-1-yl)-2-butanol as described in Example 40, and
0.35 ml of a 4N HCl -dioxane solution were added to the solution,
followed by stirring of the resulting mixture at room temperature
for 30 minutes. To the reaction mixture were added 250 mg of a
NaHCO.sub.3 powder, and the mixture was stirred for 10 minutes,
followed by filtration of the reaction mixture and concentration of
the filtrate under reduced pressure. The thus obtained oil was
subjected to column chromatography using 5 g of silica gel and
eluted with 10% methanol-ethyl acetate to obtain 179 mg (yield:
88%) of the title compound as a viscous oil.
[0240] Specific rotation [.alpha.].sub.D.sup.25 -61.degree.
(c=1.05, CHCl.sub.3)
[0241] IR spectrum .nu..sub.max(CHCl.sub.3)cm.sup.-1: 3400, 1618,
1500. NMR spectrum (60 MHz, CDCl.sub.3+D.sub.2O) .delta. ppm: 1.20
(3H, d, J=6.5 Hz), 3.0-4.0 (6H, m), 4.80 (1H, d, J=14 Hz), 5.16
(1H, d, J=14 Hz), 6.6-7.0 (2H, m), 7.43 (1H, td, J=9, 8 Hz), 7.74
(1H, s), 7.86 (1H, s).
REFERENCE EXAMPLE 3
Trans-5-[(4-chlorobenzyl)thio]-2-phenyl-1,3-dioxane
[0242] 245
[0243] After 240 mg (5.50 mmol) of 55% sodium hydride were washed
with hexane, it was suspended in 15 ml of dimethylformamide and 903
mg (5.70 mmol) of 4-chlorobenzylmercaptane were added to the
resulting suspension with stirring under nitrogen atmosphere. After
15 minutes, 1.66 g (4.96 mmol) of
cis-5-(p-toluenesulfonyloxy)-2-phenyl-1,3-dioxane were added to the
mixture and the resulting mixture was stirred at 75.degree. C. for
1 hour. After cooling, benzene was added to the reaction mixture
and the mixture was washed with water and then an aqueous NaCl
solution. After the solvent was distilled off, the thus obtained
crystalline residue was recrystallized from a mixed solvent of
benzene-hexane to obtain 670 mg (yield: 42%) of the title compound
having a melting point of 95 to 99.degree. C. as a flaky
crystalline solid.
[0244] NMR spectrum (60 MHz, CDCl.sub.3) .delta. ppm: 3.02 (1H, tt,
J=11, 5 Hz), 3 (2H, t, J=11 Hz), 3.72 (2H, s), 4.21 (2H, dd, J=11,
5 Hz), 5.39 (1H, 7.30 (5H, s), 7.38 (4H, s).
REFERENCE EXAMPLE 4
2-[(4-Chlorobenzyl)thio]-1,3-propanediol
[0245] 246
[0246] In 10 ml of methanol were dissolved 750 mg of trans-5
chlorobenzyl)thio]-2-phenyl-1,3-dioxane, and 1 ml of a 4N hydrogen
chloride-dioxane solution was added to the solution, followed by
stirring of the resulting mixture at room temperature for 1 hour.
After 750 mg of sodium hydrogencarbonate (powder) were added to the
reaction mixture and the resulting mixture was stirred for 15
minutes, the solid was removed by filtration and the solvent was
distilled off. Ethyl acetate was added to the residue and the
insolubles were removed by filtration. The crystal obtained by
evaporation of the solvent was recrystallized from a mixed solvent
of benzene-hexane to obtain 468 mg (yield: 86%) of the title
compound having a melting point of 70 to 75.degree. C.
REFERENCE EXAMPLE 5
Trans-5-[(4-chlorobenzyl)thio]-2-[(E)-1-methyl-2-[4-(trifluoromethyl)pheny-
l]vinyl]-1,3-dioxane
[0247] 247
[0248] In 12 ml of benzene were dissolved 341 mg (1.46 mmol) of
2-[(4-cblorobenzyl)thio]-1,3-propanediol and 375 mg (1.75 mmol) of
(E)-4-(trifluoromethyl)-.alpha.-methylcinnamaldehyde, and 3 mg of
p-toluenesulfonic acid were added to the solution, followed by
heating of the resulting mixture with reflux under nitrogen
atmosphere for 2 hours. After cooling, the reaction mixture was
washed with an aqueous sodium hydrogencarbonate solution. The
residue obtained by evaporation of the solvent was subjected to
column chromatography using 15 g of silica gel. The fractions
eluted with a mixed solvent of hexane-ethyl acetate (9:1) were
collected and the thus obtained solid was washed with hexane to
obtain 370 mg (yield: 59%) of the title compound having a melting
point of 93 to 95.degree. C.
[0249] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1. 87 (3H,
s) , 2. 99 (1H, tt, J=11.2, 4.6 Hz), 3.58 (2H, dd, J=11.9, 11.2
Hz), 3.73 (2H, s), 4.15 (2H, dd, J=11.9, 4.6 Hz), 4.87 (1H, s),
6.68 (1H, br s), 7.25-7.3 (4H, m), 7.36 (2H, d, J=7.9 Hz), 7.57
(2H, d, J=7.9 Hz).
REFERENCE EXAMPLE 6
Trans-5-[(4-chlorobenzyl)sulfinyl]-2-[(E)-1-methyl-2-[4-(trifluoromethyl)p-
henyl]vinyl]-1,3-dioxane
[0250] 248
[0251] In 10 ml of methylene chloride were dissolved 382 mg (0.89
mmol) of
trans-5-[(4-chlorobenzyl)thio]-2-[(E)-1-methyl-2-(4-(trifluoromethyl)phen-
yl]vinyl]-1,3-dioxane, and 188 mg (0.92 mmol) of m-chloroperbenzoic
acid (purity: 85%) were added to the solution, followed by stirring
of the resulting mixture for 15 minutes. The reaction mixture was
washed with an aqueous sodium hydrogencarbonate solution and the
solid obtained by evaporation of the solvent was washed with a
mixed solvent of ethyl acetate-hexane to obtain 328 mg (yield: 83%)
having a melting point of 192 to 194.degree. C.
[0252] NMR spectrum (60 MHz, CDCl.sub.3) .delta. ppm: 1.88 (3H, d,
J=1.5 Hz), 2.8-3.3 (1H, m), 3.8-4.5 (4H, m), 4.01 (2H, s), 4.95
(1H, s), 6.73 (1H, br s), 7.15-7.75 (8H, m).
REFERENCE EXAMPLE 7
Trans-4-(acetylthio)-2-[(E)-1-methyl-2-[4-(trifluoromethyl)pheny]vinyl]-1,-
3-dioxane
[0253] 249
[0254] In 8 ml of a mixed solvent of tetrahydrofuran-acetonitrile
(1:1) were dissolved 309 mg (0.696 mmol) of
trans-5-[(4-chlorobenzyl)sulfinyl]--
2-[(E)-1-methyl-2-[4-(trifluoromethyl)phenyl]vinyl]-1,3-dioxane,
and 500 mg (4.67 mmol) of 2,6-lutidine were added to the solution.
To the resulting mixture were added dropwise 500 mg (2.4 mmol) of
trifluoroacetic anhydride with stirring at 0.degree. C. for about 5
minutes. After 10 minutes, about 5 ml of an aqueous sodium
hydrogencarbonate solution were added to the reaction mixture and
the mixture was stirred at 5 minutes, followed by extraction with
ethyl acetate. An oily residue (about 350 mg) obtained by
evaporation of the solvent was dissolved in 5 ml of methylene
chloride and 210 mg of triethylamine were added to the solution at
0.degree. C., followed by addition of 109 mg of acetyl chloride to
the resulting mixture. After 5 minutes, the reaction mixture was
washed with water and the solvent was distilled off. The residue
was subjected to column chromatography using 10 g of silica gel and
eluted with a mixed solvent of hexane-benzene (1:1 to 1:2) to
obtain 186 mg (yield: 77%) of the title compound as a crystalline
solid. The crystalline solid was recrystallized from a mixed
solvent of benzene-hexane to obtain a plate-like crystalline solid
having a melting point of 128 to 129.degree. C.
[0255] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.92 (3H,
s), 2.36 (3H, s), 3.70 (2H, t, J=11.2 Hz), 3.96 (1H, tt, J=11.2,
4.6 Hz), 4.25 (2H, dd, J=11.2, 4.6 Hz), 4.94 (1H, s), 6.70(1H, br
s), 7.39 (2H, d, J=8.2 Hz), 7.59 (2H, d, J=8.2Kz).
REFERENCE EXAMPLE 8
Ethyl
(2E,4E)-3-methyl-5-[4-(trifluoromethyl)phenyl]-2,4-pentadienoate
[0256] 250
[0257] After 45 mg (1.03 mmol) of 55% sodium hydride were washed
with hexane, it was suspended in 3 ml of 1,2-dimethoxyethane and
273 mg (1.03 mmol) of triethyl 3-methyl-4-phosphonocrotonate were
added to the resulting mixture with stirring at 0.degree. C. under
nitrogen atmosphere. After 15 minutes, 100 mg (0.57 mmol) of
4-(trifluoromethyl)benaldehyde were added to the mixture and the
resulting mixture was stirred for 10 minutes. After ice-water was
added to the reaction mixture, the mixture was extracted with ethyl
acetate. The crude product obtained by evaporation of the solvent
was subjected to column chromatography using 5 g of silica gel and
eluted with a mixed solvent of ethyl acetate-hexane (4:96) to
obtain 159 mg (yield: 97%) of a 5:1 mixture of the title compound,
a (2E,4E) isomer and a (2Z,4E) isomer as an oil.
[0258] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: (2E, 4E)
-isomer, 1.31 (3H, t, J=6.6 Hz), 2.41 (3H, s), 4.20 (2H, q, J=6.6
Hz), 5.95 (1H, s), 6.86 (1H, d, J=16.5 Hz), 6.95 (1H, d, J=16.5
Hz), 7.5-7.65 (4H, m): (2E, 4E)-isomer (main signal), 2.14 (3H, s),
5.82 (1H, s), 6.92 (1H, d, J=16.5 Hz), 8.49 (1H, d, J=16.5 Hz).
REFERENCE EXAMPLE 9
(2E,4E)-3-Methyl-5-[4-(trifluoromethyl)phenyl]-2,4-pentadien-1-ol
[0259] 251
[0260] After a solution in which 150 mg (0.53 mmol) of ethyl
(4E)-3-methyl-5-[4-(trifluoromethyl)phenyl]-2,4-pentadienoate
((2E)/(2Z)=5/1) as described in Reference example 8 were dissolved
in 2 ml of toluene was stirred at 0.degree. C., 0.7 ml (1.06 mmol)
of a 1.5M diisobutyl aluminum hydride-toluene solution were added
to the solution. After 20 minutes, ice-water was added to -the
reaction mixture and the mixture was stirred for 10 minutes. The
insolubles were removed by filtration using Celite and the filtrate
was extracted with ethyl acetate and dried, followed by evaporation
of the solvent to obtain an oil. The oil was subjected to colum
chromatography using 5 g of silica gel and eluted with a mixed
solvent of 30 to 40% ethyl acetate-hexane to obtain 90 mg of the
title compound as an oil.
[0261] NMR spectrum (270 MMz, CDCl.sub.3) .delta. ppm: 1.34 (1H, br
s), 1.93 (3H, s), 4.37 (2H, d, J=6.5 Hz), 5.87 (1H, t, J=6.5 Hz),
6.58 (1H, d, J=16.1 Hz), 6.88 (1H, d, J=16.1 Hz), 7.50 (2H, d,
J=8.5 Hz), 7.57 (2H, d, J=8.5 Hz).
REFERENCE EXAMPLE 10
(2E, 4E)-3-Methyl-5-[4-(trifluoromethyl)phenyl]-2,4-pentadienal
[0262] 252
[0263] In 10 ml of methylene chloride were dissolved 460 mg (1.90
mmol) of
(2E,4E)-3-methyl-5-[4-(trifluoromethyl)phenyl]-2,4-pentadien-1-ol,
and 5 g of active manganese dioxide were added to the mixture,
followed by stirring of the resulting mixture at room temperature
for 30 minutes. The solid was removed by filtration, and after the
filtrate was concentrated, it was purified over silica gel
chromatography (eluting solvent: 4% ethyl acetate-hexane) to obtain
460 mg of the title compound as an oil.
[0264] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 2.41 (3H,
s), 6.13 (1H, d, J=8.0 Hz), 6.96 (1H, d, J=16.1 Hz), 7.09 (1H, d,
J=16.1 Hz), 7.55-7.7 (4H, m), 10.19 (1H, d, J=8.0 Hz).
REFERENCE EXAMPLE 11
4-(Acetylthio)-1-(tert-butoxycarbonyl)piperidine
[0265] 253
[0266] In 40 ml of dimethylformamide were dissolved 4.12 g (14.7
mmol) of 1-(tert-butoxycarbonyl)-4-(methanesulfonyloxy)piperidine,
and 2.53 g (2.21 mmol) of potassium thioacetate were added to the
solution, followed by stirring of the resulting mixture at
105.degree. C. for 4 hours under nitrogen atmosphere. After
cooling, the reaction mixture was diluted with ethyl acetate and
washed with water and then a saturated aqueous NaCl solution,
followed by evaporation of the solvent. The thus obtained residue
was subjected to silica gel column chromatography and the fractions
eluted with a mixed solvent of hexane-etnyl acetate (5:1) were
collected to obtain 5.19 g (yield: 81%) of the title compound as an
oil.
[0267] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.46 (9H,
s), 1.5-1.6 (2H, m), 1.9-2.0 (2H, m), 2.33 (3H, s), 3.0-3.1 (2H,
m), 3.5-3.7 (1H, m), 3.8-3.9 (2H, m) Mass spectrum m/e: 259, 244,
216, 202, 186, 183, 160, 144, 127, 116, 97, 84, 57.
REFERENCE EXAMPLE 12
1-(tert-Butoxycarbonyl)-4-mercaptopiperidine
[0268] 254
[0269] In dry methanol were dissolved 520 mg (2 mmol) of
4-(acetylthio)-1-(tert-butoxycarbonyl)piperidine, and 420 .mu.l (2
mmol) of a 28% sodium methoxide-methanol solution were added to the
mixture under ice-cooling and under a nitrogen atmosphere, followed
by stirring of the resulting mixture for 40 minutes. Then, 173
.mu.l of acetic acid were added to the mixture and the solvent was
distilled off at room temperature, followed by diluting of the
residue with ethyl acetate. The mixture was washed successively
with an aqueous sodium hydrogencarbonate solution and an aqueous
NaCl solution in the order and the solvent was distilled off to
obtain 430 mg of reddish orange oil. This product was used for a
subsequent reaction without purification.
[0270] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.46 (9H,
s), 1.5-1.6 (2H, m), 1.9-2.0 (2H, m), 2.8-3.0 (3H, m), 3.9-4.1 (2H,
m). Mass spectrum m/e: 217, 202, 184, 161, 144, 127, 117, 84,
82.
REFERENCE EXAMPLE 13
(2R,3R)-2-(2,4-Difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-3-[[1-(tert-butox-
ycarbonyl)piperidin-4-yl]thio]-2-butanol
[0271] 255
[0272] In 6 ml of dimethylformamide was dissolved 1-
(tert-butoxycarbonyl)-4-mercaptopiperidine (corresponding to 2
mmol) as described in Reference example 12, and 86 mg (1.97 mmol)
of 55% sodium hydride were added to the solution at 0.degree. C.
under a nitrogen atmosphere, followed by stirring of the resulting
mixture at the same temperature for 20 minutes. Then, 503 mg (2.00
mmol) of
(2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]-
oxirane were added to the reaction mixture and the mixture was
stirred at 60.degree. C. for 3 hours. After cooling, ethyl acetate
was added to the reaction mixture to dilute it and washed
successively with water and a saturated aqueous NaCl solution. An
oil obtained by evaporation of the solvent was subjected to silica
gel column chromatography and eluted with ethyl acetate to obtain
557 mg (yield: 53%) of the desired compound as an oil.
[0273] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.17 (3H, d,
J=6.6 Hz), 1.47 (9H, s), 1.4-1.6 (2H, m), 1.9-2.1 (2H, m), 2.9-3.1
(3H, m), 3.34 (1H, q, J=6.6 Hz), 3.9-4.1 (2H, m), 4.77 (1H, s),
4.82 (1H, d, J=14.2 Hz), 5.09 (1H, d, J=14.2 Hz), 6.7-6.8 (2H, m),
7.3-7.4 (1H, m), 7.77 (1H, s), 7.82 (1H, s). IR spectrum
.nu..sub.max.sup.KBrcm.sup.-1: 3401, 1691. Mass spectrum m/e: 468,
408, 395, 365, 321, 284, 253, 224, 188, 166, 144, 127.
REFERENCE EXAMPLE 14
(2R,3R)-2-(2,4-Difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)
-3-[(piperidin-4-yl)thio]-2-butanol dihydrochloride
[0274] 256
[0275] In 20 ml of ethyl acetate were dissolved 557 mg (1.05 mmol)
of
(2R,3R)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-3-[[1-(tert-buto-
xycarbonyl)piperidin-4-yl]thio]-2-butanol, and 2.63 ml (10.5 mmol)
of a 4N hydrogen chloride-ethyl acetate solution were added to the
solution, followed by stirring of the resulting mixture at
40.degree. C. for 8 hours. After cooling, the precipitated solid
was collected by filtration and washed with hexane to obtain 460 mg
(yield: 100%) of the desired compound as a colorless powder.
[0276] NMR spectrum (270 Mbz, DMSO-d6+CMCl.sub.3) .delta. ppm: 1.23
(3H, d, J=6.6 Hz), 1.8-2.0 (2H, m), 2.3-2.5 (2H, m), 3.1-3.4 (3H,
m), 3.74 (1H, q, J=6.6 Hz), 4.79 (1H, d, J=14.2 Hz), 5.05 (1H, d,
J=14.2 Hz), 5.3-5.6 (1H, br s), 6.8-6.9 (1H, m), 7.0-7.1 (1H, m),
7.2-7.3 (1H, m), 7.79 (1H, s) , 8.28 (1H, s). IR spectrum
.nu..sub.max.sup.KBrcm.sup.-1: 3366, 3094, 2725, 2483. Mass
spectrum m/e: 368, 308, 286, 284, 253, 224, 213, 183, 165, 144,
116, 113, 84.
REFERENCE EXAMPLE 15
4-(Acetylthio)piperidine hydrochloride
[0277] 257
[0278] In 45 ml of ethyl acetate were dissolved 1.25 g (4.82 mmol)
of 4-(acetylthio)-1-(tert-butoxycarbonyl)piperidine as described in
Reference example 11, and 12.0 ml (48.2 mmol) of a 4N hydrogen
chloride-ethyl acetate solution were added to the solution,
followed by stirring of the resulting mixture at 50.degree. C. for
4 hours. After cooling, the precipitated solid was collected by
filtration and washed with hexane to obtain 885 mg (yield: 94%) of
the desired compound as a slightly yellow powder.
[0279] NR spectrum (270 MHz, CD.sub.3OD) .delta. ppm: 1.8-2.0 (2H,
m), 2.1-2.3 (2H, m), 2.35 (3H, s), 3.1-3.3 (2H, m), 3.3-3.5 (2H,
m), 3.6-3.8 (1H, m).
REFERENCE EXAMPLE 16
4-(Acetylthio)-1-[(E)-4-(trifluoromethoxy)cinnamoyl]-piperidine
[0280] 258
[0281] In 17 ml of dichloromethane were suspended 1.28 g (6.53
mmol) of 4-(acetylthio)piperidine hydrochloride, and 2.27 ml (16.3
mmol) of triethylamine were added dropwise to the suspension with
stirring under ice-cooling. Then, a solution in which 1.80 g (7.18
mmol) of (E)-4-(trifluoromethoxy)cinnamoyl chloride were dissolved
in 6 ml of dichloromethane was added dropwise to the reaction
mixture, followed by stirring of the mixture at the same
temperature for 1 hour. The reaction mixture was subjected to
silica gel column chromatography and eluted with a mixed solvent of
hexane-ethyl acetate (2:1 to 1:1) to obtain 2.32 g (yield: 95%) of
the desired compound as a slightly yellow solid.
[0282] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.5-1.7 (2H,
m), 1.9-2.1 (2H, m), 2.34 (3H, s) , 3.1-3.3 (1H, m), 3.3-3.5 (1H,
m), 3.7-3.8 (1H, m), 3.9-4.0 (1H, m), 4.2-4.4 (1H, m), 6.85 (1H, d,
J=15.5 Hz), 7.21 (2H, d, J=8.63 Hz), 7.54 (2H, d, J=8.6 Hz), 7.63
(1H, d, J=15.5 Hz). Mass spectrum m/e: 373, 330, 298, 256, 228,
215, 187, 158, 136, 116, 101.
REFERENCE EXAMPLE 17
3-(Acetylthio)-1-(tert-butoxycarbonyl)azetidine
[0283] 259
[0284] An orange oil obtained from
1-(tert-butoxycarbonyl)-3-(methanesulfo- anyoxy)azetidine according
to the procedure of Reference example 11.
[0285] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.44 (9H,
s), 2.33 (3H, s), 3.81 (2H, dd, J=9.0, 5.5 Hz), 4.1-4.2 (1H, m),
4.37 (2H, t, J=9.0 Hz).
REFERENCE EXAMPLE 18
(2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[1-(tert-butox-
ycarbonyl)azetidin-3 -yl]thio]-2-butanol
[0286] 260
[0287] A pale yellow foam obtained from
3-(acetylthio)-1-(tert-butoxycarbo- nyl)azetidine according to the
procedure of Reference examples 12 and 13.
[0288] NMR spectrum (270 MHz, (CDCl.sub.3) .delta. ppm: 1.13 (3H,
d, J=7.1 Hz), 1.45 (9H, s), 3.27 (1H, q, J=7.1 Hz), 3.7-3.9 (2H,
m), 3.9-4.0 (1H, m), 4.2-4.4 (2H, m), 4.84 (1H, d, J=14.1 Hz), 4.98
(1H, s), 5.04 (1H, d, J=14.1 Hz), 6.7-6.9 (2H, m), 7.3-7.4 (1H, m),
7.78 (1H, s), 7.80 (1H, s). IR spectrum
.nu..sub.max.sup.KBrcm.sup.-1: 3405, 1701. Mass spectrum m/e; 441,
425, 385, 367, 341, 311, 284, 252, 224, 199, 183, 165, 141, 127,
88.
REFERENCE EXAMPLE 19
(2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[azetidin-3-yl)-
thio]-2-butanol dihydrochloride
[0289] 261
[0290] A slightly yellow powder obtained from
(2R,3R)-2-(2,4-difluoropheny-
l)-1-(1H-1,2,4-triazol-1-yl)-3-[[1-(tert-butoxycarbonyl)azetidin-3-yl]tbio-
]-2-butanol according to the procedure of Reference example 14.
[0291] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.16 (3H, d,
J=6.6 Hz), 3.52 (1H, q, J=6.6 Hz), 3.9-4.3 (3H, m), 4.3-4.6 (2H,
m), 4.98 (1H, d, J=14.2 Hz), 5.43 (1H, d, J=14.2 Hz), 6.6-6.9 (2H,
m), 7.2-7.4 (1H, m), 8.40 (1H, s), 8.95 (1H, s), 9.0-9.6 (1H,
br).
REFERENCE EXAMPLE 20
Ethyl trans-4-(trifluoromethyl)cinnamate
[0292] 262
[0293] After 903 mg (20.7 mmol) of 55% sodium hydride were washed
with hexane, it was suspended in 60 ml of 1,2-dimethoxyethane, and
4.63 g (20.7 mmol) of triethyl phosphonoacetate were added dropwise
thereto while the suspension was stirred at 0.degree. C. under
nitrogen atmosphere. After 15 minutes, 2.00 g (11.5 mmol) of
4-(trifluoromethyl)benzaldehyde were added to the resulting mixture
at the same temperature, followed by stirring of the mixture for 15
minutes. Ethyl acetate was added to the reaction mixture and the
resulting mixture was washed with water. After drying, an oily
residue obtained by evaporation of the solvent was subjected to
column chromatography using silica gel and eluted with 4% ethyl
acetate-hexane to obtain the title compound having a melting point
of 31 to 32.5.degree. C. in a yield of 98%.
[0294] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.35 (3H, t,
J=7.3 Hz), 4.48 (2H, q, J=7.3 Hz), 6.51 (1H, d, J=16.2 Hz), 7.66
(4H, s), 7.69 (1H, d, J=16.2 Hz).
REFERENCE EXAMPLE 21
Trans-4-(trifluoromethyl)cinnamyl alcohol
[0295] 263
[0296] In 15 ml of toluene were dissolved 3.00 g (12.3 mmol) of
ethyl trans-4-(trifluoromethyl)cinnamate, and 16.4 ml (24.6 mmol)
of a 1.5M diisobutyl aluminum hydride-toluene solution were added
to the solution with stirring at 0.degree. C. After 20 minutes,
ice-water was added to the reaction mixture and the mixture was
stirred for 10 minutes, followed by removal of the insolubles by
filtration using Celite. The filtrate was extracted with ethyl
acetate and, after drying, the solvent was distilled off to obtain
a crystalline residue. The residue was recrystallized from a mixed
solvent of benzene-hexane to obtain 2.36 g (yield: 96%) of the
title compound having a melting point of 53 to 55.degree. C.
[0297] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.55 (1H, t,
J=5.9 Hz), 4.37 (2H, br t), 6.46 (1H, dt, J=16.2, 5.3 Hz), 6.67
(1H, d, J=16.2 Hz), 7.46 (2H, d, J=8.3 Hz), 7.57 (2H, d, J=8.3
Hz).
REFERENCE EXAMPLE 22
Trans-4-(trifluoromethyl)cinnamaldehyde
[0298] 264
[0299] In 30 ml of methylene chloride were dissolved 2.15 g of
trans-4-(trifluoromethyl)cinnamyl alcohol, and 14 g of active
manganese dioxide were added to the solution at 0.degree. C.,
followed by stirring of the resulting mixture for 15 minutes and
then stirring at room temperature for 2 hours. The solid was
removed by filtration and the filtrate was concentrated to obtain a
crystalline residue. The residue was recrystallized from a mixed
solvent of benzene-hexane to obtain the title compound having a
melting point of 60 to 61.degree. C. in a yield of 90%.
[0300] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 6.78 (1H,
dd, J=16.2, 7.3 Hz), 7.53 (1H, d, J=16.2 Hz), 7.69 (4H, s), 9.76
(1H, d, J=7.3 Hz). IR spectrum .nu..sub.max (KBr) cm.sup.-1: 1680,
1630, 1321, 1173, 1123, 1066. Mass spectrum m/e: 200 (M.sup.+),
199, 171, 151, 145, 131 (100%), 103, 102.
REFERENCE EXAMPLE 23
Ethyl (2E,4E)-5-[4-(trifluoromethyl)phenyl]-2,4-pentadiencate
[0301] 265
[0302] After 4.51 g (103 mmol) of 55% sodium hydride were washed
with hexane, it was suspended in 70 ml of 1,2-dimethoxyethane, and
25.9 g (103 mmol) of triethyl phosphonocrotonate were added
dropwise thereto while the suspension was stirred at 0.degree. C.
under nitrogen atmosphere. After 15 minutes, 10.0 g (57.4 mmol) of
4-(trifluoromethyl)benzaldehyde was added to the resulting mixture
at the same temperature and the mixture was stirred for 10 minutes.
The reaction mixture was poured in ice-water, followed by
extraction with ethyl acetate. The oily residue obtained by
evaporation of the solvent was subjected to column chromatography
using silica gel and eluted with 6% ethyl acetate-hexane to obtain
11.2 g (yield: 72%) of the title compound as an oil.
[0303] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.32 (3H, t,
J=7.3 Hz), 4.24 (2H, q, J=7.3 Hz), 6.05 (1H, d, J=15.2 Hz),
6.85-7.0 (2H, m), 7.44 (1H, ddd, J=15.2, 7.9, 2.6 Hz), 7.55 (2H, d,
J=8.6 Hz), 7.61 (2H, d, J=8.6 Hz).
REFERENCE EXAMPLE 24
(2E,4E)-5-[4-(Trifluoromethyl)phenyl]-2,4-pentadien-1-ol
[0304] 266
[0305] Ethyl
(2E,4E)-5-[4-(trifluoromethyl)phenyl]-2,4-pentadienoate was treated
with diisobutyl aluminum hydride in the same manner as in Reference
example 21 to obtain the title compound in quantitative yield.
[0306] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.47 (1H, t,
J=5.9 Hz), 4.28 (2H, t, J=5.9 Hz), 6.04 (1H, dt, J=15.2, 5.9 Hz),
6.45 (1H, dd, J=15.2, 10.6 Hz), 6.57 (1H, d, J=15.8 Hz), 6.87 (1H,
dd, J=15.8, 10.6 Hz), 7.47 (2H, d, J=8.6 Hz), 7.56 (2H, d, J=8.6
Hz).
REFERENCE EXAMPLE 25
(2E,4E)-5-[4-(Trifluoromethyl)phenyl]-2,4-pentadienal
[0307] 267
[0308] (2E,4E)-5-[4-(Trifluoromethyl)phenyl]-2,4-pentadien-1-ol was
treated with active manganese dioxide in the same manner as in
Reference example 22 to obtain the title compound in a yield of
92%.
[0309] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 6.33 (1H,
dd, J=15.2, 7.3 Hz), 7.0-7.35 (3H, m), 7.60 (2H, d, J=8.6 Hz), 7.64
(2H, d, J=8.6 Hz), 9.65 (1H, d, J=7.3 Hz).
REFERENCE EXAMPLE 26
Ethyl
(2E,4E,6E)-7-[4-(trifluoromethyl)phenyl]-2,4,6-heptatrienoate
[0310] 268
[0311] (2E,4E)-5-[4-(Trifluoromethyl)phenyl]-2,4-pentadienal was
reacted with triethyl phosphonoacetate in the same mazmer as in
Reference example 20 to obtain the title compound in a yield of
95%.
[0312] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.31 (3H, t,
J=7.3 Hz), 4.23 (2H, q, J=7.3 Hz), 5.96 (1H, d, J=15.2 Hz), 6.49
(1H, dd, J=15.2, 11.2 Hz), 6.72 (1H, dd, J=15.2, 10.6 Hz), 6.73
(1H, d, J=15.8 Hz), 6.94 (1H, dd, J=15.8, 10.6 Hz), 7.37 (1H, dd,
J=15.2, 11.2 Hz), 7.51 (2H, d, J=8.6 Hz), 7.58 (2H, d, J=8.6
Hz).
REFERENCE EXAMPLE 27
(2E,4E, 6E)-7-[4-(Trifluoromethyl)phenyl]-2,4,6-heptatrien-1-ol
[0313] 269
[0314] Ethyl
(2E,4E,6E)-7-[4-(trifluoromethyl)phenyl]-2,4,6-heptatrienoate was
treated with diisobutyl aluminum hydride in the same masser as in
Reference example 21 to obtain the title compound in a yield of
90%.
[0315] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.41 (1H, t,
J=5.3 Hz), 4.25 (2H, t, J=5.3 Hz), 5.95 (1H, dt, J=15.0, 5.3 Hz),
6.3-6.5 (3H, m), 6.57 (1H, d, J=15.2 Hz), 6.90 (1H, m), 7.47 (2H,
d, J=8.6 Hz), 7.55 (2H, d, J=8.6 Hz).
REFERENCE EXAMPLE 28
(2E,4E, 6E)-7-[4- (Trifluoromethyl)phenyl]-2,4,6-heptatrienal
[0316] 270
[0317] (2E,
4E,6E)-7-[4-(Trifluoromethyl)phenyl]-2,4,6-heptatrien-1-ol was
treated with active manganese dioxide in the same manner as in
Reference example 22 to obtain the title compound in a yield of
88%.
[0318] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 6.23 (1H,
dd, J=15.2, 7.9 Hz), 6.62 (1H, dd, J=14.5, 11.2 Hz), 6.82 (1H, d,
J=15.8 Hz), 6.84 (1H, dd, J=14.5, 9.9 Hz), 6.98 (1H, dd, J=15.8,
9.9 Hz), 7.19 (1H, dd, J=15.2, 11.2 Hz), 7.54 (2H, d, J=8.6 Hz),
7.61 (2H, d, J=8.6 Hz), 9.62 (1H, d, J=7.9 Hz).
REFERENCE EXAMPLE 29
4-(2,2,3,3-Tetrafluoropropoxy)benzaldehyde
[0319] 271
[0320] After 1.90 g (43.5 mnol) of 55% sodium hydride were washed
with hexane, it was suspended in 25 ml of N,N-dimethylacetamide and
5.3 g (43 mmol) of 4-hydroxybenzaldehyde were gradually added to
the suspension at 0.degree. C. under nitrogen atmosphere. When
generation of hydrogen gas stopped, 11.14 g (39 mmol) of
2,2,3,3-tetrafluoropropyl p-toluenesulfonate were added to the
reaction mixture, followed by heating of the resulting mixture at
120.degree. C. with stirring for 2 hours and 15 minutes. After the
reaction mixture was cooled, a mixed solvent of benzene-hexane
(1:1) was added thereto and the resulting mixture was washed with
water. After drying, the solvent was distilled off to obtain 8.85 g
(yield: 96%) of the title compound as an oil.
[0321] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 4.45 (2H, br
t, J=11.9 Hz), 6.06 (1H, tt, J=53.3, 4.6 Hz), 7.06 (2H, d, J=8.7
Hz), 7.88 (2H, d, J=8.7 Hz), 9.93 (1H, s).
REFERENCE EXAMPLE 30
Ethyl
(2E,4E)-5-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-pentadienoate
[0322] 272
[0323] 4-(2,2,3,3-Tetrafluoropropoxy)benzaldehyde and triethyl
phosphonocrotonate were reacted in the same manner as in Reference
example 23 to obtain the title compound having a melting point of
65 to 66.degree. C. in a yield of 74%.
[0324] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.31 (3H, t,
J=7.3 Hz), 4.23 (2H, q, J=7.3 Hz), 4.37 (2H, br t, J=11.9 Hz), 5.95
(1H, d, J=15.2 Hz), 6.06 (1H, tt, J=53.5, 4.6 Hz), 6.77 (1H, dd,
J=15.2, 9.9 Hz), 6.86 (1H, d, J=15.2 Hz), 6.91 (2H, d, J=8.6 Hz),
7.42 (1H, dd, J=15.2, 9.9 Hz), 7.44 (2H, d, J=8.6 Hz).
REFERENCE EXAMPLE 31
(2E,4E)-5-[4-(2,2,3,3-Tetrafluoropropoxy)phenyl]-2,4-pentadien-1-ol
[0325] 273
[0326] Ethyl
(2E,4E)-5-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-pentadie-
noate was treated with diisobutyl aluminum hydride in the same
maaner as in Reference example 21 to obtain the title compound
having a melting point of 95 to 97.degree. C. in a yield of
95%.
[0327] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.39 (1H, t,
J=.about.5 Hz), 4.25 (2H, t, J=5.9 Hz), 4.34 (2H, br t, J=11.9 Hz),
5.94 (1H, dt, J=15.1, 5.9 Hz), 6.06 (1H, tt, J=53.2, 4.8 Hz), 6.40
(1H, dd, J=15.1, 10.3 Hz), 6.50 (1H, d, J=15.5 Hz), 6.69 (1H, dd,
J=15.5, 10.3 Hz), 6.88 (2H, d, J=8.7 Hz), 7.36 (2H, d, J=8.7
Hz).
REFERENCE EXAMPLE 32
(2E,4E)-5-[4-(2,2,3,3-Tetrafluoropropoxy)phenyl]-2,4-pentadienal
[0328] 274
[0329] Ethyl
(2E,4E)-5-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-pentadie-
n-1-ol was treated with active manganese dioxide in the same manner
as in Reference example 22 to obtain the title compound having a
melting point of 53 to 55.degree. C. in a yield of 96%.
[0330] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 4.38 (2H, br
t, J=11.9 Hz), 6.06 (1H, tt, J=52.8, 4.6 Hz), 6.25 (1H, dd, J=15.2,
7.9 Hz), 6.90 (1H, dd, J=15.8, 9.2 Hz), 6.94 (2H, d, J=8.6 Hz),
6.97 (1H, d, J=15.8 Hz), 7.25 (1H, dd, J=15.2, 9.2 Hz), 7.48 (2H,
d, J=8.6 Hz), 9.61 (1H, d, J=7.9 Hz).
REFERENCE EXAMPLE 33
Trans-4-(trifluoromethoxy)cinnamaldehyde
[0331] 275
[0332] 570 mg (3.0 mmol) of 4-(trifluoromethoxy)benzaldehyde and
913 mg (3.0 mmol) of (triphenylphosphoranylidene)acetaldehyde were
heated under reflux in 7.5 ml of toluene under nitrogen atmosphere
for 1 hour and 45 minutes. The toluene was distilled off under
reduced pressure and the thus obtained residue was purified over
column chromatography using 20 g of silica gel. The fractions
eluted with a mixed solvent of acetic acid-hexane (1:10) were
collected to obtain 387 mg (yield: 60%) of the title compound as an
oil.
[0333] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 6.70 (1, dd,
J=15.8, 7.3 Hz), 7.29 (2H, d, J=8.6 Hz), 7.47 (1H, d, J=15.8 Hz),
7.61 (2H, d, J=8.6 Hz), 9.72 (1H, d, J=7.3 Hz). IR spectrum
.nu..sub.max (CHCl.sub.3) cm.sup.-1: 1680, 1508, 1259. Mass
spectrum m/e: 216 (M.sup.+), 215, 187, 175, 162, 131(100%), 119,
101.
REFERENCE EXAMPLE 34
Ethyl 6-(2,2,3,3-tetrafluoropropoxy)nicotinate
[0334] 276
[0335] After 840 mg (19.3 mmol) of 55% sodium hydride were washed
with hexane, it was suspended in 40 ml of dimethylformamide, and
3.00 g (22.7 mmol) of 2,2,3,3-tetrafluoropropanol were gradually
added to the suspension at 0.degree. C. under a nitrogen
atmosphere. When generation of hydrogen gas stopped, a solution in
which 3.40 g (18.3 mmol) of ethyl 6-chloronicotinate was dissolved
in 15 ml of dimethylformamide was added dropwise to the resulting
mixture at the same temperature for about 30 minutes. After the
dropwise addition, the mixture was stirred for 30 minutes and the
reaction mixture was poured into ice-water, followed by extraction
with benzene. After the extract was dried, the solvent was
distilled off and the thus obtained oil was purified over column
chromatography [eluted with a mixed solvent of benzene-hexane
(1:1)] using silica gel to obtain 4.42 g (yield: 86%) of the title
compound as an oil.
[0336] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.40 (3H, t,
J=7.2 Hz), 4.39 (2H, q, J=7.2 Hz), 4.81 (2H, br t, J=12.6 Hz), 6.00
(1H, tt, J=53.0, 4.6 Hz), 6.87 (1H, d, J=8.6 Hz), 8.24 (1H, dd,
J=8.6, 2.5 Hz), 8.83 (1H, d, J=2.5 Hz). IR spectrum .nu..sub.max
(CHCl.sub.3) cm.sup.-1: 1717, 1604, 1280, 1119. Mass spectrum m/e:
281 (M.sup.+), 236(100%), 180, 152, 151, 123, 122, 93.
REFERENCE EXAMPLE 35
2-(2,2,3,3-Tetrafluoropropoxy)-5-(hydroxymethyl)pyridine
[0337] 277
[0338] Ethyl 6-(2,2,3,3-tetrafluoropropoxy)nicotinate was reduced
with diisobutyl aluminum hydride in the same manner as in Reference
example 21 to obtain the title compound as an oil in a yield of
100%.
[0339] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.69 (1H, t,
J=5.8 Hz), 4.66 (2H, d, J=5.8 Hz), 4.74 (2H, br t, J=12.8 Hz), 6.01
(1H, tt, J=53.1, 4.6 Hz), 6.84 (1H, d, J=8.5 Hz), 7.69 (1H, dd,
J=8.5, 2.5 Hz), 8.12 (1H, d, J=2.5 Hz). Mass spectrum m/e: 239
(M.sup.+), 210, 188, 168, 138(100%) , 109, 108, 78.
REFERENCE EXAMPLE 36
6-(2,2,3,3-Tetrafluoropropoxy)nicotinaldehyde
[0340] 278
[0341] 2-(2,2,3,3-Tetrafluoropropoxy)-5-(hydroxymetbyl) pyridine
was treated with active manganese dioxide in the same mamer as in
Reference example 22 to obtain the title copound as an oil in a
yield of 96%.
[0342] NMR spectrum (270 Mz, CDCl.sub.3) .delta. ppm: 4.86 (2H, br
t, J=12.8 Hz) , 6.01 (1H, tt, J=53.3, 4.4 Hz) , 6.97 (1H, d, J=8.6
Hz), 8.15 (1H, dd, J=8.6, 2.3 Hz), 8.65 (1H,d, J=2.3 Hz). Mass
spectrum m/e: 237 (M.sup.+), 186, 166, 136 (100%), 107, 106,
78.
REFERENCE EXAMPLE 37
(2E,4E)-5-[6-(2,2,3,3-Tetrafluoropropoxy)-3-pyridyl]-2,4-pentadienal
[0343] 279
[0344] Following Reference examples 23, 24 and 25, the title
compound having a melting point of 88 to 89.degree. C. was obtained
from 6-(2,2,3,3-tetrafluoropropoxy)nicotinaldehyde in 3 steps.
[0345] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 4.78 (2H, br
t, J=12.6 Hz), 6.01 (1H, tt, J=53.3, 4.5 Hz), 6.28 (1H, dd, J=15.2,
7.9 Hz), 6.87 (1H, d, J=8.7 Hz), 6.85-7.0 (2H, m), 7.25 (1H, ddd,
J=15.2, 7.8, 2.5 Hz), 7.85 (1H, dd, J=8.7, 2.5 Hz), 8.23 (1H, d,
J=2.5 Hz), 9.63 (1H, d, J=7.9 Hz). IR spectrum .nu..sub.max
(CHCl.sub.3) cm.sup.-1: 1677, 1626, 1591, 1488, 1290, 1120. Mass
spectrum m/e: 289 (M.sup.+), 260, 188, 178, 160, 145, 128, 117, 81,
69(100%).
REFERENCE EXAMPLE 38
(2E,4E)-5-(6-Chloro-3-pyridyl)-2,4-pentadienal
[0346] 280
[0347] Following Reference examples 23, 24 and 25, the title
compound was obtained as an oil from 6-chloronicotinaldehyde in 3
steps.
[0348] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 6.32 (1H,
dd, J=15.2, 7.8 Hz), 6.96 (1H, d, J=15.4 Hz), 7.05 (1H, dd, J=15.4,
9.8 Hz), 7.26 (1H, dd, J=15.2, 9.8 Hz), 7.36 (1H, d, J=8.3 Hz),
7.80 (1H, dd, J=8.3, 2.5 Hz), 8.48 (1H, d, J=2.5 Hz), 9.66 (1H, d,
J=7.8 Hz).
REFERENCE EXAMPLE 39
[4-[(4 -Chlorobenzyl)thio]cyclohexylidene]methyl methyl ether
[0349] 281
[0350] After 146 mg (3.34 mmol) of 55% sodium hydride were washed
with hexane, it was suspended in 18 ml of dimethyl sulfoxide,
followed by stirring of the resulting suspension at 55.degree. C.
for 2 hours. The mixture was cooled to room temperature and 1.26 g
(3.34 mmol) of methoxyrethyltriphenylphosphonium chloride were
added to the mixture. Further, a solution in which 426 mg (1.67
mmol) of 4-[(4-chlorobenzyl)thio]cyclohexanone were dissolved in 5
ml of dimethyl sulfoxide was added to the resulting mixture. Water
was added to the mixture and the resulting mixture was extracted
with toluene. After the extract was dried, the crude product
obtained by evaporation of the solvent was subjected to column
chromatography using 20 g of silica gel and eluted with a mixed
solvent of methylene chloride-hexane (1:4) to obtain 370 mg (yield:
78%) of the title compound as an oil.
[0351] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.2-1.5 (2H,
m), 1.7-2.0 (3H, m), 2.0-2.2 (1H, m), 2.5-2.8 (2H, m), 3.53 (3H,
s), 3.71 (2H, s), 5.77 (1H, s), 7.27 (4H, s). IR spectrum
.nu..sub.max (CHCl.sub.3) cm.sup.-1: 2935, 1689, 1491, 1443, 1123.
Mass spectrum m/e: 282, 157, 124, 109.
REFERENCE EXAMPLE 40
Trans-4-[(4-chlorobenzyl)thio]cyclohexanecarboxaldehyde
[0352] 282
[0353] In 20 ml of acetone were dissolved 955 mg (3.4 mmol) of
[4-[(4-chlorobenzyl)thio]cyclohexylidene]methyl methyl ether, and 5
ml of water were added to the solution, followed by addition of 1
ml of 5N hydrochloric acid. The mixture was stirred at 55.degree.
C. for 20 minutes. The mixture was concentrated under reduced
pressure and the residue was extracted with ethyl acetate. After
the extract was dried, the crude product obtained by evaporation of
the solvent was subjected to column chromatography using 15 g of
silica gel and eluted with a mixed solvent of methylene
chloride-hexane (1:3) to obtain 865 mg (yield: 95*) of a 1:1
mixture of a trans isomer, the title compound, and a cis isomer as
an oil.
[0354] This product was stirred in 15 ml of a 0.07N sodium
methoxide-methanol solution at room temperature for 2 to 3 hours.
To the mixture was added 0.2 ml of acetic acid, and the resulting
mixture was diluted with ethyl acetate and washed with an aqueous
NaCl solution. After the mixture was dried, the solvent was
distilled off to obtain 865 mg of a 4:1 mixture of the title trans
form and a cis form as a solid. The solid was recrystallized from a
mixed solvent of ether-hexane to obtain 220 mg of the trans form
title compound having a melting point of 44 to 46.degree. C.
[0355] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.2-1.5 (4H,
m), 1.9-2.15 (2H, m), 2.15-2.35 (1H, m), 2.35-2.55 (1H, m), 3.73
(2H, s), 7.27 (5H, s), 9.61 (1H, s). Cis isomer exhibited a signal
at .delta. 3.67 (2H, s) and .delta. 9.64 (1H, s). IR spectrum
.nu..sub.max (CHCl.sub.3) cm.sup.-1: 2927, 1732, 1493, 1448, 1092.
Mass spectrum m/e: 268, 240, 127, 125, 110.
REFERENCE EXAMPLE 41
4-Chlorobenzyl
trans-4-[(1E,3E)-4-[4-(trifluoromethyl)phenyl]-1,3-butadien-
yl]cyclohexyl sulfide
[0356] 283
[0357] After 50 mg (1.14 mmol) of 55% sodium hydride were washed
with hexane, it was suspended in 7 ml of dimethyl sulfoxide,
followed by stirring of the suspension at 55.degree. C. for 2.5
hours. The mixture was cooled to room temperature and 607 mg (1.26
=mmol) of [(E)-4-(trifluoromethyl)cinnamyl]triphenylphosphonium
chloride were added thereto. Further, 170 mg (0.63 mmol) of
trans-4-[(4-chlorobenzyl)thio]cyc- lohexanecarboxaldehyde were
added to the resulting mixture, followed by stirring of the mixture
at room temperature for 15 minutes. The mixture was diluted with
toluene and washed with water and an aqueous NaCl solution. After
the mixture was dried, the crude product obtained by evaporation of
the solvent was subjected to column chromatography using 5 g of
silica gel and eluted with a mixed solvent of methylene
chloride-hexane (1:2). The eluted portion was recrystallized from
hexane to obtain 86 ms (yield: 31%) of the title compound having a
melting point of 142 to 144.degree. C.
[0358] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.1-1.3 (2H,
m), 1.3-1.5 (2H, m), 1.7-2.0 (2H, m), 2.0-2.2 (2H, m), 2.64 (1H,
tt, J=12.4 Hz), 3.74 (2H, s), 5.81 (1H, dd, J=15, 7 Hz), 6.20 (1H,
dd, J=15, 10 Hz), 6.47 (1H, d, J=16 Hz), 6.81 (1H, dd, J=16, 10
Hz), 7.29 (4H, s) , 7.46 (2H, d, J=8 Hz), 7.55 (2H, d, J=8 Hz). IR
spectrum .nu..sub.max (KBr) cm.sup.-1: 1641, 1612, 1490, 1326,
1167, 1127, 1069. Mass spectrum m/e: 436, 417, 403, 311, 277, 235,
159, 125.
REFERENCE EXAMPLE 42
4-Chlorobenzyl
trans-4-[(1E,3E)-4-[4-(trifluorometbyl)phenyl]-1,3-butadien-
yl]cyclohexyl sulfoxide
[0359] 284
[0360] In 20 ml of methylene chloride were dissolved 211 mg (0.48
mmol) of 4-chlorobenzyl
trans-4-[(1E,3E)-4-[4-(trifluoromethyl)phenyl]-1,3-butadie-
nyl]lcyclohexyl sulfide, and 104 mg (0.48 mmol) of
m-chloroperbenzoic acid (purity: 80%) were added to the solution at
0.degree. C., followed by stirring of the resulting mixture for 5
minutes. An aqueous sodium sulfite solution and ethyl acetate were
added to the reaction mixture and the organic layer was washed with
an aqueous sodium hydrogencarbonate solution and an aqueous NaCl
solution. After the mixture was dried, the crude product obtained
by evaporation of. the solvent was recrystallized from a mixed
solvent of ethyl acetate-hexane to obtain 168 mg (yield: 77%) of
the title compound having a melting point of 212 to 214.degree.
C.
[0361] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.1-1.3 (2H,
m), 1.5-1.8 (2H, m), 1.9-2.3 (5H, m), 2.42 (1H, tt, J=12, 4 Hz),
3.87 (1H, d, J=13 Hz), 3.97 (1H, d, J=13 Hz), 5.80 (1H, dd, J=15, 7
Hz), 6.22 (1H, dd, J=15, 10 Hz), 6.48 (1H, d, J=16 Hz), 6.80 (1H,
dd, J=16, 10 Hz), 7.25 (2H, d, J=8 Hz), 7.36 (2H, d, J=8 Hz), 7.45
(2H, d, J=8 Hz), 7.55 (2H, d, J=8 Hz). IR spectrum .nu..sub.max
(KBr) cm.sup.-1: 1612, 1492, 1325, 1168, 1128, 1069. Mass spectrum
m/e: 452, 436, 327, 278, 277, 159, 125.
REFERENCE EXAMPLE 43
Trans-1-(acetylthio)-4-[(1E,3E)-4-[4-(trifluoromethyl)phenyl]-1,3-butadien-
-1-yl]cyclohexazne
[0362] 285
[0363] In 11 ml of a mixed solvent of tetrahydrofuran-acetonitrile
(8:3) were dissolved 178 mg (0.39 mmol) of 4-chlorobenzyl
trans-4-[(1E,3E)-4-[4-(trifluoromethyl)phenyl]-1,3-butadienyl]cyclohexyl
sulfoxide, and 168 mg (1.57 mmol) of 2,6-lutidine were added to the
solution. To the mixture were added 165 mg (0.79 mmol) of
trifluoroacetic anhydride with stirring at 0.degree. C. After 3
minutes, an aqueous sodium hydrogencarbonate solution was added to
the mixture, followed by extraction with ethyl acetate. The oily
residue obtained by evaporation of the solvent was dissolved in 10
ml of methylene chloride, and 119 mg (1.17 mmol) of triethylamine
were added to the mixture at 0.degree. C., followed by addition of
62 mg (0.79 mmol) of acetyl chloride to the resulting mixture.
After 1 hour, the reaction mixture was diluted with ethyl acetate
and washed with an aqueous sodium hydrogencarbonate solution and an
aqueous NaCl solution. After the mixture was dried, the crude
product obtained by evaporation of the solvent was subjected to
column chromatography using 5 g of silica gel and eluted with a
mixed solvent of methylene chloride-hexane (1:1), followed by
purification over Rover column [GrosseB, a mixed solvent of ethyl
acetate-hexane (1:19)] to obtain 98 mg (yield: 70%) of the title
compound having a melting point of 113 to 115.degree. C.
[0364] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.2-1.5 (4H,
m), 1.7-1.9 (2H, m), 2.0-2.2 (3H, m), 2.31 (3H, s), 3.37 (1H, tt,
J=12, 4 Hz), 5.82 (1H, dd, J=15, 7 Hz), 6.20 (1H, dd, J=15, 10 Hz),
6.47 (1H, d, J=16 Hz), 6.81 (1H, dd, J=16, 10 Hz), 7.45 (2H, d, J=8
Hz), 7.54 (2H, d, J=8 Hz). IR spectrum .nu..sub.max (KBr)
cm.sup.-1: 1688, 1613, 1326, 1157, 1117, 1068. Mass spectrum m/e:
354, 335, 311, 277, 235, 159.
REFERENCE EXAMPLE 44
3-[4-(Trifluoromethyl)phenyl]-2-propyn-1-ol
[0365] 286
[0366] In 50 ml of diethylamine were dissolved 5.0 g (22 mmol) of
4-bromo-.alpha.,.alpha.,.alpha.-trifluorotoluene and 1.25 g (22
mmol) of propargyl alcohol, and 80 mg (0.11 mmol) of
bis(triphenylphosphine)pallad- ium (II) chloride and 40 mg (0.22
mmol) of copper (I) iodide were added to the solution, followed by
stirring of the resulting mixture at 50.degree. C. for 35 minutes.
To the mixture were added 40 mg (0.06 mmol) of
bis(triphenylphosphine)palladium (II) chloride, and the resulting
mixture was stirred for a further 35 minutes. After the mixture was
cooled to room temperature, it was diluted with benzene and
filtered, and then the filtrate was washed with water. After the
mixture was dried, the crude product obtained by evaporation of the
solvent was subjected to column chromatography using 50 g of silica
gel and eluted with a mixed solvent of ethyl acetate-hexane (3:17)
to obtain 2.21 g (yield: 50%) of the title compound as an oil.
[0367] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.8 (1H, br,
OH), 4.52 (2H, s), 7.54 (2H, d, J=9 Hz), 7.57 (2H, d, J=9 Hz). IR
spectrum .nu..sub.max (CHCl.sub.3) cm.sup.-1: 3610, 1618, 1324,
1172, 1133, 1069, 1019, 844. Mass spectrum m/e: 200, 183, 171, 151,
131.
REFERENCE EXAMPLE 45
3-[4-(Trifluoromethyl)phenyl]-2-propynal
[0368] 287
[0369] In 20 ml of methylene chloride were dissolved 2.21 g (11.0
mmol) of 3-[4-(trifluoromethyl)phenyl]-2-propyn-1-ol, and 7.43 g
(17.5 mmol) of Dess-Martin reagent were added to the solution under
ice-cooling for 1.7 hours. Benzene was added to the resulting
mixture and the insolubles were removed by filtration, followed by
concentration of the filtrate to obtain 1.83 g (yield: 84%) of the
title compound as an oil.
[0370] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 7.68 (2H, d,
J=9 Hz), 7.71 (2H, d, J=9 Hz), 9.45 (1H, s). IR spectrum
.nu..sub.max (CHCl.sub.3) cm.sup.-1: 2197, 1664, 1324, 1175, 1138.
Mass spectrum m/e: 198, 197, 170, 151, 120.
REFERENCE EXAMPLE 46
Ethyl (E)-5-[(4-trifluoromethyl)phenyl]-2-penten-4-ynoate
[0371] 288
[0372] After 181 mg (4.54 mmol) of 55% sodium hydride were washed
with hexane, it was suspended in 10 ml of 1,2-dimethoxyethane, and
1.02 g (4.54 mmol) of triethyl 4-phosphonoacetate were added to the
suspension with stirring at 0.degree. C. under nitrogen atmosphere.
After 20 minutes, 500 mg (2.52 mmol) of
3-[4-(trifluoromethyl)phenyl]-2-propynal were added to the mixture,
followed by stirring of the resulting mixture for 20 minutes. The
reaction mixture was diluted with ethyl acetate, ice was added to
the mixture and then the organic layer was washed with water. The
crude product obtained by distilling off the solvent was subjected
to column chromatography using 15 g of silica gel and eluted with
benzene to obtain 488 mg (yield: 72%) of the title compound as an
oil.
[0373] NMR spectru (270 MHz, CDCl.sub.3) .delta. ppm: 1.32 (3H, t,
J=7 Hz), 4.25 (2H, q, J=7 Hz), 6.35 (1H, d, J=16 Hz), 6.97 (1H, d,
J=16 Hz), 7.5-7.7 (4H, m) IR spectrum .nu..sub.max (CHCl.sub.3)
cm.sup.-1: 1712, 1622, 1316, 1174, 1134. Mass spectrum m/e: 268,
240, 223, 195, 183, 175.
REFERENCE EXAMPLE 47
(E)-5-[4-(Trifluorometbyl)phenyl]-2-penten-4-yn-1-ol
[0374] 289
[0375] In 4 ml of toluene were dissolved 480 mg (1.79 mmol) of
ethyl (E)-5-[4-(trifluoromethyl)phenyl]-2-penten-4-ynoate, and 2.38
ml (3.58 mmol) of a 1.5 M diisobutyl aluminum hydride-toluene
solution were added to the solution with stirring at 0.degree. C.
After 10 minutes, ice was added to the mixture and the insolubles
were removed by filtration using Celite. After the organic layer
was dried, the crude product obtained by evaporation of the solvent
was subjected to column chromatography using 15 g of silica gel and
eluted with a mixed solvent of ethyl acetate-hexane (3:17) to
obtain 353 mg (yield: 87%) of the title compound as an oil.
[0376] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.60 (1H,
br, OH), 4.31 (2H, br), 5.99 (1H, d, J=16 Hz), 6.40 (1H, dt, J=16,
5 Hz), 7.54 (2H, d, J=9 Hz), 7.57 (2H, d, J=9 Hz).
REFERENCE EXAMPLE 48
(E)-5-[4-(Trifluoromethyl)phenyl]-2-penten-4-ynal
[0377] 290
[0378] In 4 ml of methylene chloride were dissolved 350 mg (1.56
mmol) of (E)-5-[4-(trifluoromethyl)phenyl]-2-penten-4-yn-1-ol, and
3.5 g of active manganese dioxide were added to the solution,
followed by stirring of the resulting mixture at room temperature
for 30 minutes. The solid was removed by filtration and the
filtrate was concentrated. Then, the filtrate was subjected to
column chromatography using 10 g of silica gel and eluted with a
mixed solvent of ethyl acetate-hexane (1:24) to obtain 245 mg
(yield: 70%) of the title compound as an oil.
[0379] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 6.58 (1H,
dd, J=16, 8 Hz), 6.82 (1H, d, J=16 Hz), 7.63 (4H, s), 9.65 (1H, d,
J=8 Hz). IR spectrum .nu.max (CHCl.sub.3) cm.sup.-1: 1670, 1325,
1132, 1119, 1107, 1072, 845. Mass spectrum m/e: 224, 196, 195, 175,
170, 146.
REFERENCE EXAMPLE 49
Methyl (Z)-4-chloro-.beta.-(trifluoromethyl)cinnamate
[0380] 291
[0381] In 10 ml of tetrahydrofuran were dissolved 150 mg (0.47
mmol) of bis(2,2,2-trifluoroethyl)
(methoxycarbonylmethyl)phosphonate, and 0.94 ml (0.47 mmol) of a
0.5 M potassium hexamethyldisilazide-toluene solution were added
dropwise to the mixture with stirring at -78.degree. C. under
nitrogen atmosphere. Then, 622 mg (2.36 mmol) of 18-crown-6 were
added to the mixture and the resulting mixture was stirred for 20
minutes, followed by addition of a solution in which 98 mg (0.47
mmol) of 4'-chloro-2,2,2-trifluoroacetophenone were dissolved in 1
ml of tetrahydrofuran. The temperature of the reaction mixture was
slowly elevated to room temperature and a saturated aqeous ammonium
chloride solution was added to the mixture, followed by extraction
with ethyl acetate. The crude product obtained by evaporation of
the solvent was purified over column chromatography (eluted with 4%
ethyl acetate-hexane) using silica gel to obtain 89 mg (yield: 70%,
containing about {fraction (1/10)} of (E)-isomer) of the title
compound as an oil.
[0382] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 3.85 (3H,
s), 6.34 (1H, s), 7.34 (2H, d, J=8.6 Hz), 7.39 (2H, d, J=8.6
Hz).
REFERENCE 50
(Z)-4-Chloro-.beta.-(trifluoromethyl)cinnamaldehyde
[0383] 292
[0384] Following Reference examples 21 and 22, the title compound
was obtained as an oil in a yield of 81% from methyl
(Z)-4-chloro-.beta.-(tri- fluoromethyl)cinnamate in 2 steps.
[0385] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 6.36 (1H, d,
J=7.3 Hz), 7.38 (2H, d, J=8.6 Hz), 7.44 (2H, d, J=8.6 Hz), 10.21
(1H, dq, J=7.3, 2.0 Hz).
REFERENCE EXAMPLE 51
Methyl
(2E,4Z)-5-(4-chlorophenyl)-6,6,6-trifluoro-2,4-hexadienoate
[0386] 293
[0387] (Z)-4-Chloro-.beta.-(trifluoromethyl)cinnamaldehyde and
trimethyl pbosphonocrotonate were reacted in the same manner as in
Reference example 23 to obtain the title compound as an oil in a
yield of about 90% (separation and purification by column
chromatography).
[0388] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 3.81 (3H,
s), 6.15 (1H, d, J=15.2 Hz), 6.59 (1H, d, J=11.9 Hz), 7.31 (2H, d,
J=8.6 Hz), 7.38 (1H, d, J=8.6 Hz), 7.78 (1H, ddq, J=15.2, 11.9, 2.0
Hz).
REFERENCE EXAMPLE 52
(2E,4Z)-5-(4-Clorophenyl)-6,6,6-trifluoro-2,4-hexadienal
[0389] 294
[0390] Following Reference examples 21 and 22, the title compound
was obtained as an oil in a yield of 71% fron methyl
(2E,4Z)-5-(4-chloropheny- l)-6,6,6-trifluoro-2,4-hexadienoate in 2
steps.
[0391] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 6.37 (1H,
dd, J=15.2, 7.3 Hz), 6.72 (1H, d, J=11.9 Hz), 7.33 (2H, d, J=8.6
Hz), 7.40 (2H, d, J=8.6 Hz), 7.64 (1H, ddq, J=15.2, 11.9, 2 Hz),
9.74 (1H, d, J=7.3 Hz).
REFERENCE EXAMPLE 53
2-Methyl-2-[(trans-2-phenyl-1,3-dioxan-5-yl)thio]-4'-(trifluoromethyl)prop-
iophenone
[0392] 295
[0393] In 3.8 ml of dimethylformamide were dissolved 619 mg (2.10
mmol) of 2-bromo-2-methyl-4'-(trifluoromethyl)propiophenone and 500
mg (2.1 mmol) of trans-4-acetylthio-2-phenyl-1,3-dioxane, and 0.44
ml (2.10 mmol) of a 28% sodium methoxide-methanol solution were
added to the solution with stirring at room temperature under
nitrogen atmosphere. After 30 minutes, water was added to the
reaction mixture and the resulting mixture was extracted with ethyl
acetate. The solvent was evaporated to obtain 860 mg (yield:
.about.100%) of the title compound as a solid.
[0394] NMR spectrun (270 MHz, CDCl.sub.3) .delta. ppm: 1.61 (6H,
s), 4.42 (1H, tt, J=11.6, 5.0 Hz), 3.64 (2H, t, J=11.6 Hz), 4.12
(2H, dd, J=11.6, 5.0 Hz), 5.38 (1H, s), 7.3-7.5 (5H, m), 7.68 (2H,
d, J=8.2 Hz), 8.19 (2H, d, J=8.2 Hz).
REFERENCE EXAMPLE 54
(RS)
-3-Methyl-3-[(trans-2-phenyl-1,3-dioxan-5-yl)thio]-1-(1H-1,2,4-triazo-
l-1-yl]-2-butanol
[0395] 296
[0396] 680 mg (1.66 mmol) of
2-methyl-2-[(trans-2-phenyl-1,3-dioxan-5-yl)
thio]-4'-(trifluoromethyl)propiophenone, 547 mg (2.49 mmol) of
trimethylsulfoxonium iodide, 381 mg (6.79 mmol) of potassium
hydroxide and 264 mg (3.82 mmol) of 1,2,4-triazole were heated with
stirring in 5.7 ml of t-butanol at 80.degree. C. for 6 hours. After
cooling, the reaction mixture was distributed between chloroform
and water and the chloroform layer was separated and dried,
followed by evaporation of the solvent. The thus obtained oil was
subjected to column chromatography using silica gel and eluted with
a mixed solvent of ethyl acetate-hexane (1:1) to obtain 605 mg
(yield: 74%) of the title compound as a foam.
[0397] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.38 (3H,
s), 1.39 (3H, s), 3.55-3.8 (3H, m), 4.33 (1H, m), 4.54 (1H, m),
5.02 (2H, s), 5.37 (1H, s), 5.44 (1H, s), 7.3-7.6 (5H, m), 7.73
(1H, s) , 7.94 (1H, s).
REFERENCE EXAMPLE 55
(RS)-3-[(1,3-Dihydroxy-2-propyl)thio]-3-methyl-2-[4-(trifluoromethyl)pheny-
l]-1-(1H-1,2,4-triazol-1-yl)-2-butanol
[0398] 297
[0399]
(RS)-3-Methyl-3-[(trans-2-phenyl-1,3-dioxan-5-yl)thio]-1-(1H-1,2,4--
triazol-1-yl)-2-butanol was treated with HCl in methanol in the
same manner as in Reference example 2 to obtain the title compound
as a foam.
[0400] NMR spectrum (270 MHz, CDCl.sub.3) .delta. ppm: 1.30 (3H,
s), 1.42 (3H, s), 3.35 (1H, m), 3.55-3.8 (3H, m), 3.96 (1H, dd,
J=10.9, 5.4 Hz), 4.83 (3H, s), 5.26 (1H, d, J=14.6 Hz), 5.34 (1H,
d, J=14.6 Hz), 7.53 (2H, d, J=8.3 Hz), 7.70 (1H, s), 7.75 (2H, d,
J=8.3 Hz), 8.26 (1H, s).
REFERENCE EXAMPLE 56
2-(p-Toluenesulfonyloxy)-1,3-propanediol
[0401] 298
[0402] In 50 ml of methanol were dissolved 5.00 g of
cis-2-phenyl-4-(p-toluenesulfonyloxy)-1,3-dioxane, and 5 ml of a 4N
HCl-dioxane solution were added to the solution, followed by
stirring of the resulting mixture at room temperature for 2 hours.
To the reaction mixture were added 3.5 g of NaHCO.sub.3 powder, and
the mixture was stirred for 10 minutes. Then, the reaction mixture
was filtered and the filtrate was concentrated under reduced
pressure. The thus obtained oil was subjected to column
chromatography using silica gel and eluted with ethyl acetate to
obtain 3.70 g (yield: 100%) of the title compound as an oil.
[0403] NMR spectrum (60 MHz, CDCl.sub.3) .delta. ppm: 2.40 (3H, s),
3.30 (2H, s), 3.73 (4H, d, J=4.5 Hz), 4.5 (1H, quintet, J=4.5 Hz),
7.33 (2H, d, J=8 Hz), 7.84 (2H, d, J=8 Hz).
REFERENCE EXAMPLE 57
Cis-4-(p-toluenesulfonyloxy)-2-[(1E,3E)-4-[4-(trifluoromethyl)phenyl]-1,3--
butadien-1-yl]-1,3-dioxane
[0404] 299
[0405] In 4.5 ml of methylene chloride were dissolved 200 mg (0.81
tmmol) of 2-(p-toluenesulfonyloxy)-1,3-propanediol and 206 mg (0.91
mmol) of (2E,4E)-5-[4-(trifluoromethyl)phenyl]-2,4-pentadienal, and
15 mg of p-toluenesulfonic acid and 0.8 g of molecular sieves 4A
were added to the solution, followed by stirring of the resulting
mixture at 0.degree. C. for 1 hour. An aqueous sodium
hydrogencarbonate solution was added to the reaction mixture and
the mixture was stirred for 10 minutes. Then, the molecular sieves
were removed by filtration and the filtrate was extracted with
methylene chloride. The oil obtained by evaporation of the solvent
was separated by preparative thin layer chromatography of silica
gel (developing solvent: 20% ethyl acetate-hexane) to obtain 107 mg
(yield: 29%) of a trans isomer having less polarity and 153 mg
(yield: 42%) of a cis isomer having higher polarity as an oil,
respectively.
[0406] NMR spectrum (270 MHz, CDCl.sub.3) of cis isomer .delta.
ppm: 2.45 (3H, s), 3.99 (2H, br d, J=13.2 Hz) , 4.19 (2H, br d,
J=13.2 Hz) , 4.45 (1H, br s) , 5.09 (1H, d, J=4.6 Hz), 5.82 (1H,
dd, J=15.2, 4.6 Hz), 6.57 (1H, dd, J=15.2, 10.5 Hz), 6.63 (1H, d,
J=15.2 Hz), 6.82 (1H, dd, J=15.2, 10.5 Hz) , 7.36 (2H, d, J=8.6 Hz)
, 7.48 (2H, d, J=8.6H) , 7.56 (2H, d, J=8.6 Hz), 7.85 (2H, d, J=8.6
Hz).
TEST EXAMPLE 1
[0407] To mice (one group consisting of 10 mice), which were
innoculated with 4 to 9.times.10.sup.6 Candida albicans, were
administered orally 20 mg/kg of preparations after 1, 4 and 24
hours, and thereafter the survival rate until 21 days after
infection was examined. The results of comparison of the compound
(I) of the present invention with commercially available Fluconazol
are shown in Table 2. From the results, it is apparent that the
compound (I) exhibits an excellent antifungal activity.
2 TABLE 2 Survival rate % Compound 14 days 21 days Example 2 100
100 11 100 100 15 100 100 16 100 100 18 100 100 21 100 60 30 100
100 32 100 100 35 100 100 37 100 100 Fluconazol 70 60
PREPARATION EXAMPLE 1
[0408]
3 Capsule Compound of Examples 1 to 39 or 40 50 mg Lactose 128 mg
Corn starch 70 mg Magnesium stearate 2 mg 250 mg
[0409] The thus formulated powder was mixed and passed through a
sieve of 60 mesh, and then the powder was encapsulated in No. 3
gelatin capsule of 250 mg to prepare a capsule.
PREPARATION EXAMPLE 2
[0410]
4 Tablet Compound of Examples 1 to 39 or 40 50 mg Lactose 126 mg
Corn starch 23 mg Magnesium stearate 1 mg 200 mg
[0411] The thus formulated powder was mixed and wet-granulated
using a corn starch sizing agent and dried, and then a 200
mg-tablet was made by means of a tablet making machine. If
necessary, sugar coating can be applied to the tablet.
[0412] The compound having the general formula (I) or a
pharmacologically acceptable salt thereof of the present invention
has an excellent antifungal activity and is useful as an antifungal
agent.
* * * * *