SPECIFICATION
PROCESS FOR PRODUCTION OF ETHYLENEDIAMINE DERIVATIVES HAVING
HALOGENATED CARBAMATE GROUP AND ACYL GROUP, AND INTERMEDIATES FOR
5 PRODUCTION OF THE DERIVATIVES
TECHNICAL FIELD
[0001]
The field of the present invention relates to a process for
10 producing ethylenediamine derivatives having a halogenated
carbamate groupand anacylgroup, and intermediates for production
of the derivatives.
BACKGROUND ART
15 [00021
There has been known that ethylenediamine derivatives having a
halogenated carbamate group and an acyl group is useful as a
fungicide as shownin Patent Document 1. To prepare such a compound
group, it is very important to produce ethylenediamine derivatives
20 having a carbamate group that are intermediates for production of
- - b
the compound thereof with good efficiency.
[0003]
Examples of the conventional technique for production of
ethylenediamine derivatives having a carbamate group include (I)
25 a process including converting amino alcohols having a carbamate
-
group into a phthalimide adduct using phthalimide,
triphenylphosphine and diethylazodicarboxylate, and then
subjecting the phthalimide adduct to deprotection with hydrazine
(Non-patent Document I), (11) a process including carrying out the
catalytic hydrogenation of aminonitriles having a carbamate group
in an ethanol solvent saturated with ammonia in the presence of
Raney nlckel (Non-patent Document 2) and the like.
5 Patent Document 1: W02005042474
Non-patent Document 1: Tetrahedron Asymmetry, Vol. 11, pp. 1907
to 1910, 2000
Non-patent Document 2: Synthetic Communications, Vol. 24, No.
12, pp. 1767 to 1772, 1994
10
DISCLOSURE OF THE INVENTION
[0004]
Since the aforementioned process (I) as described in Non-patent
Document 1 employs diethylazodicarboxylate or hydrazine which has
15 a problem in that a plurality of and any amount of reaction
by-products are produced and a problem in the safety, it is
difficult to mention that it is suitable for an industrial process
On the other hand, the aforementioned process (11) as described
in Non-patent Document 2 is excellent in the yield, and also has
20 an advantage in the industrial production process. However, when
the aforementioned process (11) is applied, for example, to
aminonitriles having a halogen-substituted carbamate group such
as a 2,2,2-trifluoroethoxycarbonylaminonitrile derivative, it has
been made clear, as a result of the review by the present inventors,
25 that z ccmpound obtained hy converting-a carbamate group into-_a
areidogroup is obtained even without progressing the intended
-=-.=A..-L< --. reactio n.
In other words, since the halogen-substituted carbamate group
has good reactivity as compared to usual hydrocarbon-based
carbamate groups, it has turned out that it is extremely difficult
to apply the prior art. It has become clear that the reactivity
5 at this time becomes a problem in common when a compound group
having a halogen-substituted carbamate group is produced as well
as when the reduction reaction of nitrile is conducted. For that
reason, a production progress with good efficiency needs to be
developed for every production intermediates.
! 10 [0005]
The present invention is to solve a novel object of effectively
producing ethylenediamine derivatives having a halogenated
carbamate group and an acyl group, and to provide a process which
is favorable to the industrial production of the ethylenediamine
15 derivatives.
[0006]
The present inventors have conducted an extensive study and as
a result, have found an effective solution to the above object by
carrying out the catalytic hydrogenation of aminonitriles having
20 a halogen-substituted carbamate group in the presence of an acid
and then performing the acylation of the resulting product.
Furthermore, we have found that the aminonitriles are prepared in
a high yield by performing the halogenated carbamatation of amino
acidamides in the presenceof water andthenreactingthe resulting
. . . 25 prod-ct vith a deoxldlzlng agent such as a ~rilsmeier reaqent. Thus:
the present invention has been completed.
[x?7]
That is, t h e p r e s e n t i n v e n t i o n is s p e c i f i e d b y m a t t e r s d e s c r i b e d
i n below:
[I] a p r o c e s s f o r producing a compoundrepresentedbythegeneral
formula ( 4 ) comprising;
5 c o n v e r t i n g t h e compound r e p r e s e n t e d by t h e g e n e r a l formula (1)
i n t o a compound r e p r e s e n t e d by t h e g e n e r a l formula (2) by
performing t h e c a t a l y t i c hydrogenation o f a compound r e p r e s e n t e d
by t h e general formula (1) i n t h e presence of an a c i d , and
r e a c t i n g t h e compound r e p r e s e n t e d by t h e g e n e r a l formula (2)
10 with a compound r e p r e s e n t e d by t h e g e n e r a l formula (31,
[OOOE]
wherein, i n t h e formula, R1 r e p r e s e n t s an a l k y l group having I
15 t o 6 carbon atoms which is s u b s t i t u t e d with a t l e a s t one halogen
atom o r a c y c l o a l k y l group having 3 t o 6 carbon atoms which is
s u b s t i t u t e d with a t l e a s t one halogen atom; .R2 r e p r e s e n t s a
hydrogen atom, an a l k y l group having 1 t o 6 carbon atoms, a
c y c l o a l k y l group having 3 t o 6 carbon atoms, an a r y l group which
20 may be s u b s t i t u t e d o r a h e t e r o a r y l group vrhich may be s u b s t i t u t e d ;
R3 and R4 each independently r e p r e s e n t a hydrogen atom, an a l k y l
g r o u p h a v i n g 1 t o 6 carbon atoms which may be s u b s t i t u t e d , a
c y c l o a l k y l group having 3110 6 carbon atoms which may be s i ~ b s t i t i u t e d ;
an a r y l group which may be s u b s t i t u t e d , an a r y l a l k y l group which
25 :zy be s u b s t i t u t e d , 2 h e t e r o a r y l group which may be s u b s t i t u t e d
o r a h e t e r o a r y l a l k y l group which may be s u b s t i t u t e d ; and R3 and
.R4 may be bonded with each o t h e r t o form a r i n g s t r u c t u r e having
3 t o 6 carbon atoms, o r any one of R3 and R4 may be bonded with
R2 t o form a r i n g s t r u c t u r e having 5 t o 6 atoms i n t o t a l (4 t o 5
5 carbon atoms and 1 n i t r o g e n atom),
[OOlO]
wherein, i n t h e formula, R1, R2, R3 and R4 a r e t h e same a s those
10 d e s c r i b e d above,
wherein, i n t h e formula, R5 r e p r e s e n t s an a l k y l group having 1
15 t o 6 carbon atoms which may b e s u b s t i t u t e d , a c y c l o a l k y l group
having 3 t o 6 carbon atoms which may be s u b s t i t u t e d , an a r y l group
which may be s u b s t i t u t e d , an a r y l a l k y l group which may be
s u b s t i t u t e d , a h e t e r o a r y l group which may be s u b s t i t u t e d or a
. h e t e r o a r y l a l k y l group which may be s u b s t i t u t e d ; and X r e p r e s e n t s
20 a l e a v i n g group,
[00141 ~~ ~~ ~ ~ ~ ~ ~
[0015]
wherein, in the formula, R1, R2, R3, R4 and R5 are the same as
those described above;
[2] the process for producing a compound represented by the
5 general formula (4) as set forth in [I], in vihlch the compound
represented by the general formula (1) is obtained by reacting a
compound represented by the general formula (5) with a deoxidizing
agent,
[00161
[0017]
wherein, in the formula, R1, R2, R3 and R4 are the same as those
described above;
131 the process for producing a compound represented by the
15 general formula (4) as set forth in [2], in which the compound
represented by the general formula (5) is obtained by reacting a
compound represented by the general formula (6) with a compound
represented by the general formula (7) in the presence of water,
[0018]
R3 R4
[0019]
wherein, in the formula, R2, R3 and R4 are the same as those
described above,
[00201
[0021]
5 vrherein, in the formula, R1 is the same as those described above;
and Y represents a halogen atom;
[4] the process for producing a compound represented by the
,
general formula (4) as set forth in [I], in which, in the formulas,
R1 represents an alkyl group having 1 to 6 carbon atoms which is
10 substituted with at least one halogen atom; R2 represents a
hydrogen atom or an alkyl group having 1 to 6 carbon atoms; R3 and
R4 each independently represent a hydrogen atom, an alkyl group
having 1 to 6 carbon atoms which may be substituted, an aryl group
which may be substituted or an arylalkyl group which may be
15 substituted, and any one of R3 and R4 may be bonded with R2 to form
a ring structure having 5 to 6 atoms in total (4 to 5 carbon atoms
and 1 nitrogen atom); and R5 represents an aryl group which may
I/
be substituted or a heteroaryl group which may be substituted;
[5] the process for producing a compound represented by the
20 general formula (4) as set forth in [2], in which, in the formulas,
R1 represents an alkyl group having 1 to 6 carbon atoms which is
substituted with at least one halogen atom; R2 represents a
hydrogen atom-or an alkyl group having-1t o~_6Ccarbonat oms; R3an11---
R4 each independently represent a hydrogen atom, an alkyl group
25 having 1 to 5 czrbon atoms which may be substituted, an aryl group
which may be substituted or an arylalkyl group which may be
substituted, and any one of R3 and R4 may be bonded with R2 to form
a ring structure having 5 to 6 atoms in total (4 to 5 carbon atoms
and 1 nitrogen atom); and R5 represents an aryl group which may
5 be substituted or a heteroaryl group which may be substituted;
[6] the process for producing a compound represented by the
general formula (4) as set forth in [3], in which, in the formula,
R1 represents an alkyl group having 1 to 6 carbon atoms which is
substituted with at least one halogen atom; R2 represents a
10 hydrogen atom or an alkyl group having 1 to 6 carbon atoms; R3 and
~4 each independently represent a hydrogen atom, an alkyl group
having 1 to 6 carbon atoms which may be substituted, an aryl group
which may be substituted or an arylalkyl group which may be
substituted, and any one of R3 and R4 may be bonded with R2 to form
15 a ring structure having 5 to 6 atoms in total (4 to 5 carbon atoms
and 1 nitrogen atom); and R5 represents an aryl group which may
be substituted or a heteroaryl group which may be substituted;
[7] the process for producing a compound represented by the
, general formula (4) as set forth in [4], in which, in the formula,
20 R1 is an alkyl group having 1 to 6 carbon atoms which is substituted
with at least one fluorine atom;
[El the process for producing a compound represented by the
general formula (4) as set forth in [5], in which, in the formula,
R1 is an alkyl group having 1 to 6 carbon atoms which is substituted
25 with at lcast one fluorine atom; ~ -~ ~
[9] the process for producing a compound represented by the
generzl for~.ula (4) as set forth in [ 6 ] , in which, in the formula,
Rl is an alkyl group having 1 to 6 carbon atoms which is substituted
with at least one fluorine atom;
[lo] a process for producing a compound represented by the
general formula (2) comprising;
5 converting the compound represented by the general formula (1)
into a compound represented by the general formula (2) by
performing the catalytic hydrogenation of a compound represented
by the general formula (1) in the presence of an acid,
[0022]
[0023]
wherein, in the formula, R1, R2, R3 and R4 are the same as those
described in [I],
[0024]
wherein, in the formula, R1, R2, R3 and R4 are the same as those
described in [I] ;
[ll] the process for producing a compound represented by the
20 general formula (2) as set forth in [lo], in r.ihich, in the formulas,
Rl represents an alkyl group having 1. to 6 carbon atoms -. r.~hichi s
substituted with at least one halogen atom; R2 represents a
hydrogen ztom or an alkyl group having 1 to 6 carbon atoms; and
R3 and R4 each independently r e p r e s e n t a hydrogen atom, an a l k y l
group havlng 1 t o 6 carbon atoms vrhich may be s u b s t i t u t e d , an a r y l
group whlch may be s u b s t i t u t e d o r an a r y l a l k y l group vrhich may be
s u b s t i t u t e d , and any one of R3 and R4 may be bonded with R2 t o form
5 a r i n g s t r u c t u r e having 5 t o 6 atoms i n t o t a l ( 4 t o 5 carbon atoms
and 1 n i t r o g e n atom);
[12] t h e process f o r producing a compound r e p r e s e n t e d by t h e
g e n e r a l formula ( 2 ) as s e t f o r t h i n [ I l l , i n which, i n t h e formula,
R1 is an a l k y l group having 1 t o 6 carbon atoms which is s u b s t i t u t e d
10 brith a t least one f l u o r i n e atom;
[13] a process f o r producing a compound r e p r e s e n t e d by t h e
g e n e r a l formula (1) comprising;
c o n v e r t i n g t h e r e s u l t i n g product i n t o a compound r e p r e s e n t e d b y
t h e g e n e r a l formula (1) by r e a c t i n g a compound r e p r e s e n t e d by t h e
15 g e n e r a l formula (5) krith a d e o x i d i z i n g agent,
[0026]
[0027]
wherein, i n t h e formula, R1, R2, R3 and R4 a r e t h e same a s t h o s e
20 d e s c r i b e d i n [Z],
[0028]
wherein, in the formula, R1, R2, R3 and R4 are the same as those
described in [2];
[14] the process for producing a compound represented by the
general formula (1) as set forth in [13], in which, in the formulas,
5 RI represents an alkyl group having 1 to 6 carbon atoms which is
substituted with at least one halogen atom; R2 represents a
hydrogen atom or an alkyl group having 1 to 6 carbon atoms; and
R3 and R4 each independently represent a hydrogen atom, an alkyl
group having 1 to 6 carbon atoms which may be substituted, an aryl
10 group which may be substituted or an arylalkyl group which may be
substituted, and any one of R3 and R4 may be bonded with R2 to form
a ring structure having 5 to 6 atoms in total (4 to 5 carbon atoms
and 1 nitrogen atom) ;
[I51 the process for producing a compound represented by the
15 general formula (1) as set forth in [14], in which, in the formula,
R1 is an alkyl group having 1 to 6 carbon atoms which is substituted
with at least one fluorine atom;
[16] a process for producing a compound represented by the
general formula (5) comprising;
20 converting the resulting product into a compound represented by
the general formula (5) by reacting a compound represented by the
general formula (6) with a compound represented by the general
formula ( I ) in the presence of water,
[0030]
wherein, in the formula, R2, R3 and R4 are the same as those
described in [31,
wherein, in the formula, R1 and Y are the same as those described
in [31,
LO0341
LO0351
wherein, in the formula, R1, R2, R3 and R4 are the same as those
described in [3];
[17] the process for producing a compound represented by the
15 general formula (5) as set forth in [16], in which, in the formulas,
R1 represents an alkyl group having 1 to 6 carbon atoms which is
substituted with at least one halogen atom; R2 represents a
hydrogen atom or an alkyl group having 1 to 6 carbon atoms,; and
R3 and R4 each independently represent a hydrogen atom, an alkyl
20 group having 1 to 6 carbon atoms which may be substituted, an aryl
~ -~
group which may be substituted or an arylalkyl group which may be
substituted, and any one of R3 and R4 may be bonded with R2 to form
a ring structure having 5 to 6 atoms in total (4 to 5 carbon atoms
and 1 n i t r o g e n atom);
[I81 t h e process f o r producing a compound r e p r e s e n t e d by t h e
g e n e r a l formula (5) a s set f o r t h i n [17], i n which, i n t h e formula,
R1 is a n a l k y l group having 1 t o 6 carbon atoms which is s u b s t i t u t e d
5 with a t l e a s t one f l u o r m e atom;
[19] a compound r e p r e s e n t e d by t h e g e n e r a l formula ( 2 ) ,
100371
10 wherein, i n t h e formula, R1 r e p r e s e n t s an a l k y l group having 1
t o 6 carbon atoms which is s u b s t i t u t e d with a t l e a s t one f l u o r i n e
atom o r a c y c l o a l k y l group having 3 t o 6 carbon atoms which is
s u b s t i t u t e d w i t h a t l e a s t one f l u o r i n e atom; R2 r e p r e s e n t s a
hydrogen atom, an a l k y l group having 1 t o 6 carbon atoms, a
15 c y c l o a l k y l group having 3 t o 6 carbon atoms, an a r y l group which
may he s u b s t i t u t e d or a h e t e r o a r y l group which may be s u b s t i t u t e d ;
R3 and R4 each independently r e p r e s e n t a hydrogen atom, an a l k y l
group having 1 t o 6 carbon atoms which may be s u b s t i t u t e d , a
c y c l o a l k y l g r o u p h a v i n g 3 t o 6 carbonatoms whichmaybe s u b s t i t u t e d ,
20 an a r y l group which may be s u b s t i t u t e d , an a r y l a l k y l group which
may be s u b s t i t u t e d , a h e t e r o a r y l group which may be s u b s t i t u t e d
o r a h e t e r o a r y l a l k y l group which may be s u b s t i t u t e d ; and R3 and
R4 may he bonded with each o t h e r t o form a r i n g s t r u c t u r e h a v i n g ~
3 t o 6 carbon atoms, o r any one of R3 and R4 may be bonded with
25 R2 t o form a r i n g s t r u c t u r e having 5 t o 6 atoms i n t o t a l (4 t o 5
carbon atoms and 1 nitrogen atom);
[20] the compound represented by the general formula (2) as set
forth in [19], wherein, in the formula, Rlrepresents analkylgroup
havlng 1 to 6 carbon atoms which is substltuted with at least one
5 fluorine atom; R2 represents a hydrogen atom or an alkyl group
having 1 to 6 carbon atoms; and R3 and R4 each independently
representa hydrogen atom, an alkylgrouphaving 1to 6 carbon atoms
which may be substituted, an aryl group which may be substituted
or an arylalkyl group which may be substituted, and any one of R3
10 and R4 may be bonded with R2 to form a ring structure having 5 to
6 atoms in total (4 to 5 carbon atoms and 1 nitrogen atom);
[211 a compound represented by the general formula (I),
15 [0039]
wherein, in the formula, R1 represents an alkyl group having 1
to 6 carbon atoms which is substituted V~ith at least one fluorine
'atom or a cycloalkyi group hav2ng 3 to 6 carbon atoms which is
substituted with at least one fluorine atom; R2 represents a
20 hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a
cycloalkyl group having 3 to 6 carbon atoms, an aryl group which
may be substituted or a heteroaryl group which may be substituted;
R3 and '4 each independently represent a hydrogen atom, an alkyl -
group having 1 to 6 carbon atoms whlch may be substltuted, a
25 cycloalkylgrouphavir?g 3to 6 carbonatoms c~hichmaybes ubstituted,
an aryl group which may be substituted, an arylalkyl group .which
may be substituted, a heteroaryl group which may be substituted
or a heteroarylalkyl group which may be substituted; and R3 and
R4 may be bonded with each other to form a ring structure having
5 3 to 6 carbon atoms, or any one of R3 and R4 may be bonded with
R2 to form a ring structure having 5 to 6 -atoms in total (4 to 5
carbon atoms and 1 nitrogen atom);
[221 the compound represented by the general formula (1) as set
forth in [21], wherein, in the formula, Rl represents an alkyl group
10 having 1 to 6 carbon atoms which is substituted with at least one
fluorine atom; R2 represents a hydrogen atom or an alkyl group
having 1 to 6 carbon atoms; and R3 and R4 each independently
represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms
which may be substituted, an aryl group which may be substituted
15 or an arylalkyl group which may be substituted, and any one of R3
and R4 may be bonded with R2 to form a ring structure having $ to
6 atoms in total (4 to 5 carbon atoms and 1 nitrogen atom);
[23] a compound represented by the general formula (5),
[0040]
[0041]
wherein, in the-formula, R1 represents represent~ s~ ~a-~n alkyl ~ gr~-o~u~ p having 1
to 6 carbon atoms which is substituted with at least one fluorine
atom or a cycloalkyl group having 3 to 6 carbon atoms which is
25 sobstituted with at least one fluorine atom; R2 represents a
hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a
cycloalkyl group having 3 to 6 carbon atoms, an aryl group which
may be substituted or a heteroaryl group vrhich may be substituted;
R3 and R4 each Independently represent a hydrogen atom, an alkyl
5 group hav~ng 1 to 6 carbon atoms which may be substituted, a
cycloalkylgrouphaving 3to 6 carbon atoms brhichmaybe substituted,
an aryl group which may be substituted, an arylalkyl group which
may be substituted, a heteroaryl group which may be substituted
or a heteroarylalkyl group which may be substituted; and R3 and
10 R4 may be bonded w ~ t hea ch other to form a ring structure having
3 to 6 carbon atoms, or any one of R3 and R4 may be bonded with
R2 to form a ring structure having 5 to 6 atoms in total (4 to 5
carbon atoms and 1 nitrogen atom); and
[24] the compound represented by the general formula (5) as set
15 forth in [23], wherein, in the formula, Rlrepresents analkyl group
having 1 to 6 carbon atoms which is substituted with at least one
fluorine atom; R2 represents a hydrogen atom or an alkyl group
having 1 to 6 carbon atoms; and R3 and R4 each independently
representa hydrogen atom, an alkylgroup havinglto 6 carbon atoms
20 which may be substituted, an aryl group which may be substituted
or an arylalkyl group which may be substituted, and any one of R3
and R4 may be bonded with R2 to form a ring structure having 5 to
6 atoms in total (4 to 5 carbon atoms and 1 nitrogen atom).
[0042] -
According to the present invention, it is possible to provide
a novel process for prodccing ethylenediamine derivatives having
a halogenated carbamate group and an acyl group, and novel
intermediates for production of the derivatives. Furthermore, the
catalytic hydrogenation in the present invention has advantages
such that it can be a reaction capable of recycling a catalyst,
5 industrial wastes can be reduced, a reagent that is a problem in
terms of safetycanbe omitted, and the derivatives can be produced
in a high yield. For that reason, the present invention is
excellent in environmentalsustainability, economicalefficiency,
' ,
safety and productivity, and is useful as an industrial production
10 process.
BEST MODE FOR CARRYING OUT THE INVENTION
[0043]
The present invention will be described in more detail below.
15 The present invention relates to a process for producing a
compound represented by the general formula (4) comprising;
converting the compound represented by the general formula (1)
into a compound represented by the Eollov~ing general formula (2)
by performing the catalytic hydrogenation of a compound
20 represented by the following general formula (1) in the presence
of an acid, and
reacting the compound represented by the general formula (2)
with a compound represented by the general formula (3).
[0044]
[ 0 0 4 5 ]
In the formula (I), R1 represents an alkyl group having 1 to 6
carbon atoms which is substituted with at least one halogen atom
or a cycloalkyl qroup having 3 to 6 carbon atoms whlch is
5 substituted with at least one halogen atom; R2 represents a
hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a
cycloalkyl group having 3 to 6 carbon atoms, an aryl group which
may be substituted or a heteroaryl group b~hich may be substituted;
R3 and R4 each independently represent a hydrogen atom, an alkyl
' 10 group having 1 to 6 carbon atoms which may be substituted, a
cycloalkylgrouphaving 3to 6 carbon atoms whichmaybe substituted,
an aryl group which may be substituted, an arylalkyl group ~~hich
may be substituted, a heteroaryl group which may be substituted
, or a heteroarylalkyl group which may be substituted; and R3 and
15 R4 may be bonded with each other to form a ring structure having
3 to 6 carbon atoms, or any one of R3 and R4 may be bonded with
R2 to form a ring structure having 5 to 6 atoms in total (4 to 5
carbon atoms and 1 nitrogen atom)
lo0471
In the formula (2), R1, R2, R3 and R4 are the same as those
[0049]
In the formula (3), R5 represents an alkyl group having 1 to 6
carbon atoms which may be substituted, a cycloalkyl group having
5 3 to 6 carbon atoms which may be substituted, an aryl group r,rhich
may be substituted, an arylalkyl group which may be substituted,
a heteroaryl group which may be substituted or a heteroarylalkyl
group which may be substituted; and X represents a leaving group.
[OOSl]
In the formula (4), R1, R2, R3, R4 and R5 are the same as those
described above.
In the compound represented by the general formula (I), R1
15 represents an alkyl group having 1 to 6 carbon atoms which is
substituted with at least one halogen atom or a cycloalkyl group
having 3 to 6 carbon atoms which is substituted with at least one
halogen atom.
[0052]
20 The halogen atom in R1 of the general formula (1) represents
fluorinei chlorine, bromine, iodine or-the like.
I00531
Ths z l k y l grocp having 1 to 6 carbon atoms in R1 of the general
formula (1) represents a linear alkyl group such as a methyl group,
an ethyl group, a propyl group, a butyl group, a pentyl group, a
hexyl group or the like; or a branched alkyl group such as an
~sopropyl qroup, an lsobutyl group, a sec-butyl group, a
5 1-methylbutylgroup, a 2-methylbutylgroup, a 3-methylbutylgroup,
a 1,i-dimethylpropyl group, a 2,2-dimethylpropyl group, a
i,2-dimethylpropyl group, a 1-methylpentyl group, a
2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl
group, a 1,l-dimethylbutyl group, a 1,2-dimethylbutyl group, a
10 1,3-dimethylbutyl group, a 2,2-dimethylbutyl group, a
2,3-dimethylbutyl group, a 3,3-dimethylbutyl group or the like.
At least one halogen atom may be present in these alkyl groups.
When two ormoreparts of alkylgroups are s u b s t i t u t e d r . ~ i t h h a l o g e n s ,
the halogens may be the same or different. There is no particular
15 restriction in this regard.
[0054]
The cycloalkyl group having 3 to 6 carbon atoms in R1 of the
general formula (1) represents a cyclopropyl group, a cyclobutyl
group, a cyclopentyl group, a cyclohexyl group or the like.
20 [0055]
In the compound represented by the general formula (I), R2
represents a hydrogen atom, an alkyl group having 1 to 6 carbon
atoms, a cycloalkyl group having 3 to 6 carbon atoms, an aryl group
which may be substituted or a heteroaryi group which may be
25 subsiituted.
[0056]
rn zlkyl qroup having 1 to 6 carbon atoms in R2 of the general
formula (1) is the same as those described in R1 of the general
formula (1).
[0057]
The cycloalkyl group having 3 to 6 carbon atoms in R2 of the
5 general formula (1) is the same as those described in Rl of the
general formula (1) .
[0058]
Examples of the substituent in the aryl group which may be
substituted or the heteroaryl group which may be substituted in
10 R2 of the general formula (I) include alkyl groups such as a methyl
group, an ethyl group, a propyl group, an isopropyl group, a butyl
group, an isobutyl group, a sec-butyl group and the like;
cycloalkyl groups such as a cyclopropyl group, a cyclobutyl group,
a cyclopentyl group, a cyclohexyl group and the like;
15 halogen-substituted alkyl groups such as atrifluoromethyl group,
a difluoromethyl group, a bromodifluoromethyl group, a
trifluoroethyl group and the like; alkoxy groups such as a methoxy
group, an ethoxy group, a propoxy group, an isopropoxy group, a
butoxy group, an isobutoxy group, a sec-butoxy group and the like;
20 halogen-substitutedalkoxy groups suchas atrifluoromethoxygroup,
a difluoromethoxy group, a trifluoroethoxy group and the like;
alkoxycarbonyl groups such as a methoxycarbonyl group, an
ethoxycarbonyl group, a propoxycarbonyl group, an
isopropoxycarbonyl group, a butoxycarbonyl group, an
25 isobutoxycarbonyl group, a sec-butoxycarbonyl group and the like;
aryloxycarbonyl groups such as a phenoxycarbonyl group and the
like; alkylsulfonyl groups such as a methanesulfonyl group, an
ethanesulfonyl group, a propanesulfonyl group, a butanesulfonyl
group and the like; halogen-substituted alkylsulfonyl groups such
as a trifluoromethanesulfonyl group, a difluoromethanesulfonyl
group, atrifluoroethanesulfonylgroup and the like; alkylcarbonyl
5 groups such as a methylcarbonyl group, an ethylcarbonyl group, a
propylcarbonyl group, an lsopropylcarbonyl group and the like;
cycloalkylcarbonyl groups such as a cyclopropylcarbonyl group, a
cyclobutylcarbonyl group, a cyclopropylcarbonyl group, a
cyclopentylcarbonyl group, a cyclohexylcarbonyl group and the
10 like; arylcarbonyl groups such as a benzoyl group and the like;
alkylcarbonyloxy groups such as a methylcarbonyloxy group, an
ethylcarbonyloxy group, a propylcarbonyloxy group, an
isopropylcarbonyloxy group and the like; cycloalkylcarbonyloxy
groups such as a cyclopropylcarbonyloxy group, a
15 cyclobutylcarbonyloxy group, a cyclopentylcarbonyloxy group, a
cyclohexylcarbonyloxy group and the llke; and arylcarbonyloxy
groups such as a benzoyloxy group and the l~ke. The number of
substituents on the aryl group or the heteroaryl group is not
restricted. Furthermore, when two or more parts of the aryl group
20 or the heteroaryl group are substituted, the substituents may be
the same or different. There is no restriction in this regard.
[0059]
The aryl group in R2 of the general formula (1) represents a
phenyl group, a naphthyl group, an anthranil group, a phenanthryl
26 group or the like. -
[0060]
Examplss of the heteroaryl group in R2 of the general formi~la
(1) include nitrogen-containing heterocyclic groups such as a
pyridyl group, a pyrimidyl group, a pyrazolyl group, a pyrazinyl
group, a pyridazynylgroup, an imidazolylgroup, an indolyl group,
a qulnolyl group, a qulnoxalyl group, a benzimidazolyl group and
5 the like; oxygen-contalnlng heterocyclic groups such as a
tetrahydrofuranyl group, a furanyl group, a pyranyl group, a
dioxanyl group, a 2,3-dihydrobenzo[l,4]dioxynyl group, a
benzofuranyl group and the like; and heterocyclic groups
containing two or more hetero atoms such as an oxazolyl group, an
10 isoxazolyl group, a benzoxazolyl group, a benzoisoxazolyl group
and the like.
[0061]
In the compound represented by the general formula (I), R3 and
R4 each independently represent a hydrogen atom, an alkyl group
15 having 1 to 6 carbon atoms trhich may be substituted, a cycloalkyl
group having 3 to 6 carbon atoms which may be substituted, an aryl
group which may be substituted, an arylalkyl group which may be
substituted, a heteroaryl group which may be substituted or a
heteroarylalkyl group which may be substituted. Furthermore, R3
20 and R4 may be bonded with each other to form a ring structure having
3 to 6 carbon atoms, or any one of R3 and R4 may be bonded with
R2 to form a ring structure having 5 to 6 atoms in total (4 to 5
carbon atoms and 1 nitrogen atom).
[0062]
25 In R3 and R4 of the general formula (1); examples of the
substituent in the alkyl group having 1 to 6 carbon atoms which
may be substituted, the cycloalkyl group having 3 to 6 carbon atoms
r.ihich may be s u b s t i t u t e d , t h e a r y l group which may b e s u b s t i t u t e d ,
t h e a r y l a l k y l group which may be s u b s t i t u t e d , t h e h e t e r o a r y l group
w h ~ c h may be substituted o r t h e h e t e r o a r y l a l k y l group which may
be s u b s t i t u t e d ~ n c l u d ea l k y l g r o u p s s u c h a s a m e t h y l group, an e t h y l
5 group, a propyl group, an i s o p r o p y l group, a b u t y l group, an
i s o b u t y l group, a sec-butyl group and t h e l i k e ; c y c l o a l k y l groups
such a s a cyclopropyl group, a cyclobutyl group, a cyclopentyl
group, a cyclohexyl group and t h e l i k e ; h a l o g e n - s u b s t i t u t e d a l k y l
groups such a s a t r i f l u o r o m e t h y l group, a d i f l u o r o m e t h y l group,
10 a bromodifluorornethyl group, a t r i f l u o r o e t h y l group and t h e l i k e ;
alkoxy groups such as a methoxy group, an ethoxy group, a propoxy
group, an isopropoxy group, a butoxy group, an isobutoxy group,
a sec-butoxy group and t h e l i k e ; cycloalkoxy groups such as a
cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group,
15 a cyclohexyloxy group and t h e l i k e ; h a l o g e n - s u b s t i t u t e d alkoxy
groups such a s a trifluoromethoxy group, a difluoromethoxy group,
a t r i f l u o r o e t h o x y group and t h e l i k e ; alkoxycarbonyl groups such
a s a methoxycarbonyl group, an ethoxycarbonyl group, a
propoxycarbonyl group, an isopropoxycarbonyl group, a
20 butoxycarbonyl group, an isobutoxycarbonyl group, a
sec-butoxycarbonyl group and t h e l i k e ; cycloalkoxycarbonylgroups
such a s a cyclopropoxycarbonylgroup, a cyclobutoxycarbonylgroup,
a cyclopentyloxycarbonyl group, a cyclohexyloxycarbony1 group and
t h e l i k e ; aryloxycarbonyl groups such a s a phenoxycarbonyl group
25 and L h e l i k e ; a l k - y l s u l f o n y l g r o u p s s u c h a s a m e t h a n e s u l f o n y l group,^ ~
a n e t h a n e s u l f o n y l g r o u p , a propanesulfonylgroup, a b u t a n e s u l f o ~ y l
group and t h e l i k e ; h a l o g e n - s u b s t i t u t e d a l k y l s u l f o n y l qrollps such
as a trifluoromethanesulfonyl group, a difluoromethanesulfonyl
group, atrifluoroethanesulfonylgroup and the like; alkylcarbonyl
groups such as a methylcarbonyl group, an ethylcarbonyl group, a
propyl~carbonyl group, an isopropylcarbonyl group and the like;
5 cycloalkylcarbonyl groups such as a cyclopropylcarbonyl group, a
cyclobutylcarbonyl group, a cyclopropylcarbonyl group, a
cyclopentylcarbonyl group, a cyclohexylcarbonyl group and the
like; arylcarbonyl groups such as a benzoyl group and the like;
alkylcarbonyloxy groups such as a methylcarbonyloxy group, an
10 ethylcarbonyloxy group, a propylcarbonyloxy group, an
isopropylcarbonyloxy group and the like; cycloalkylcarbonyloxy
groups such as a cyclopropylcarbonyloxy group, a
cyclobutylcarbonyloxy group, a cyclopentylcarbonyloxy group, a
cyclohexylcarbonyloxy group and the like; arylcarbonyloxy groups
15 such as a benzoyloxy group and the like; and halogens such as
fluorine, chlorine, bromine, iodine and the like. As for the alkyl
group, the cycloalkyl group, the arylalkyl group, the
heteroarylalkyl group, the aryl group or the heteroaryl group, the
number of substituents is not restricted. As forthe alkyl group,
20 the cycloalkyl group, the arylalkyl group, the heteroarylalkyl
group,. the aryl group or the heteroaryl group, when two or more
parts thereof are substituted, the substituents may be the same
or different. There is no restriction in this regard. However,
R3 or R4 that is a trifluoromethyl group is excluded, and
25 halogen-subs Li Luted aromatic groups subjected to the catalytic ~ - .~
hydrogenation, for example, halogenated aryl groups such as
chlorophenyl, bromophenyl phenyl and the like, or haloqenated
heteroaryl groups such as chloropyridine and the like are also
excluded.
[0063]
The alkyl group ha~.ring 1 to 6 carbon atoms in R3 or R4 of the
5 general formula (1) is the same as those described in R1 of the
general formula (1) .
[0064]
The cycloalkyl group having 3 to 6 carbon atoms in R3 or R4 of
the general formula (1) is the same as those described in R1 of
10 the general formula (1).
[0065]
The aryl group in R3 or R4 of the general formula (1) is the same
as those described in R2 of the general formula (1).
[00661
15 In the arylalkyl group in R3 or R4 of the general formula (I),
the aryl portion thereof is the same as the aryl group described
in R2 of the general formula (I), while the alkyl portion thereof
represents an alkyl group having 1 to 4 carbon atoms.
[0067]
20 Examples of the heteroaryl group in R3 or R4 of the general
formula (1) include nitrogen-containing heterocyclic groups such
as a pyridyl group, a pyrimidyl group, a pyrazolyl group, a
pyrazinyl group, a pyridazynyl group, an irnidazolyl group, an
indolyl group, a quinolyl group, a quinoxalyl group, a
25 benzimidazolyl group and the like; oxygen-containing heterocyclic
groups such as a tetrahydrofuranyl group, a furanyl groug, a
pyranyl group, 2 dioxanyl group, a 2,3-dLhydrober?~n[1,4!dioxynyl
group, a benzofuranyl group and the like; and heterocyclic~groups
containing two or more hetero atoms such as an oxazolyl group, an
isoxazolyl group, a benzoxazolyl group, a benzoisoxazolyl group
and the like.
5 [0068]
In the heteroarylalkyl group in R3 or R4 of the general formula
(I), the heteroaryl portlon thereof is the same as the heteroaryl
group described in R2 of the general formula (I), while the alkyl
portion thereof represents an alkyl group having 1 to 4 carbon
10 atoms.
[0069]
When the compound represented by the general formula (1) has an
asymmetric carbon atom, an optically active substance or racemate
can be used.
[0070]
It is possible to perform the catalytic hydrogenation of the
compound represented by the general formula (1) in the presence
of an acid for converting the compound represented by the general
formula (1) into the compound represented by the general formula
2.0 (2) .
Accordingly, generation of a by-product can be suppressed and
the compound representedbythe general formula (2) canbe obtained
in a high yield.
[0071]
25 In the colllpound-represei~tecib y the general f0rinula-~~2),-RKl,2 ,
R3 and R4 are the same as those described in tho gfceral formula
(1) .
[0072]
Theacid in use is not restrictedas long as it does not decompose
the compound represented by the general formula (1) or (2). For
example, organic acids or inorganic acids can be used.
5 [0073]
Examples of the organic acid include formic acid, acetic acid,
methanesulfonic acid and the like, while examples of the inorganic
acid include hydrochloric acid, sulfuric acid, phosphoric acidand
the like.
10 [00741
The amount of the acid used is not restricted as long as the
intended reaction proceeds, but, it is usually from not less than
1 equivalents to not more than 20 equivalents.
LO0751
15 As a catalytic hydrogenation method, a method for carrying out
the catalytic hydrogenation with metals such as pallaclium,
platinum, rhodium, ruthenium and the like can be cited. These
metals can be used in the form of a metal oxide, a metal chloride
or the like.
20 [0076]
The amount of the metal to be used for performing the catalytic
hydrogenation method is not particularly limited as long as the
reaction proceeds, but it is preferably equal to or not more than
the weight of the general formula (1) from the economic
~~ - ~ 25 perspectives. ~ - - ~ -
100771
As the type of the metal in use, ir.etals sl~~rieirnl h n activated
carbon, SiOz, Al2O3, BaSOa, Ti02, ZrOZ, MgO, Tho2, diatomaceous earth
or the like can be used. Regardless of its type, though, it is
preferable to use a carrier which can be recycled from the economic
perspectives.
5 [0078]
Asolventtobe used for carrylngoutthe catalytichydrogenation
method is notparticularlylimited as long as the reactionproceeds.
Concrete examples thereof include alcohol solvents such as
methanol, ethanol, isopropanol and the like; aromatic solvents
10 such as benzene, toluene, xylene andthe like; hydrocarbon solvents
such as hexane, heptane and the like; amide solvents such as
dimethylformamide, dimethylacetamide, 1-methyl-2-pyrrolidone and
the like; ether solvents such as diethyl ether, diisopropyl ether,
1,2-dimethoxyethane, tetrahydrofuran, dioxane and the like; ester
15 solvents such as ethyl acetate, butyl acetate, isopropyl acetate
and the like; and water. These solvents can be used singly, or
two or more kinds thereof can be used in combination at an optional
ratio.
[0079]
20 The amount of the solvent used is not particularly limited, but
it is usually preferably from 3 to 40 times weight, based on the
weight of the general formula (1).
[OOEO]
The reaction type is not particularly limited, but it is
25 preferable that the compound presented in general formula (1) or
the compound presented in general formul~ (1) diluted with the
above solvent is added dropxwise to 2 ~ n l i ~ ~ ~ t , r o ~ t aa imnetbanl ~
and an a c i d i n the presence of a hydrogen source.
[0081]
The r e a c t i o n temperature is not p a r t i c u l a r l y l i m i t e d a s long as
t h e compound is not decomposed, but it is u s u a l l y from n o t l e s s
5 t h a n -10 t o not more than 150 degree centigrade o r not more than
t h e b o i l i n g p o i n t of a s o l v e n t .
[0082]
The r e a c t i o n p r e s s u r e is not p a r t i c u l a r l y l i m i t e d , and t h e
r e a c t i o n m a y b e c a r r i e d o u t i n an atmospheric p r e s s u r e o r an a p p l i e d
10 p r e s s u r e .
[0083]
The hydrogen source t o be used f o r t h e c a t a l y t i c hydrogenation
is not p a r t i c u l a r l y l i m i t e d a s long a s t h e r e a c t i o n proceeds, but
a t r a n s E e r hydrogenation using cyclohexene, formic a c i d , formate
15 and t h e l i k e i n a d d i t i o n t o hydrogen gas can be used.
[0084]
T h e e q u i v a l e n t of cyclohexene, f o r m i c a c i d a n d f o r m a t e t o b e u s e d
f o r c a r r y i n g out t h e r e a c t i o n by t h e t r a n s f e r hydrogenation is not
p a r t i c u l a r l y l i m i t e d a s long a s t h e amount of g e n e r a t e d hydrogen
20 is t o b e n o t l e s s than 2 e q u i v a l e n t s , but it is p r e f e r a b l y from
not l e s s than 2 e q u i v a l e n t s t o not more than 10 e q u i v a l e n t s from
t h e economic p e r s p e c t i v e s .
[0085]
The usage o f t h e compound r e p r e s e n t e d b y t h e g e n e r a l formula (2)
25 o b t a i r ~ e db y t h e above r e a c t i o n i n t h e n e x t s t e p is not p a r t j ~ c l l l a r l y
l l m i t e d . The r e a c t i o n s o l u t i o n contzir-i.; xhe conpound
r e p r e s e n t e d by t h e g e n e r a l f=rmcL;. !2! c;.~ he ' A j e c t e d t o a usual
post-treatment such as removal of a solvent, liquid separation or
the like, and then used in the next step without performing
isolation and purification, or those in the form of a salt with
an inorganic acid such as hydrochloric acid, sulfuric acid,
5 phosphoric acidor the like, or an organic acid such as oxalic acid,
fumaric acid, maleic acid, formic acid, acetic acid,
methanesulfonic acid or the like can be used in the next step
LO0861
The compound represented by the general formula (2) also
10 contains a salt formed with an inorganic acid or an organic acid.
Examples ofthe inorganic acid include hydrochloric acid, sulfuric
acid, phosphoric acid and the like, while examples of the organic
acid include oxalic acid, fumaric acid, maleic acid, formic acid,
acetic acid, methanesulfonic acid and the like.
15 LOO871
By reacting the compound represented by the general formula (2)
with the compound represented by the general formula ( 3 ) , the
resulting product can be converted into the compound represented
by the general formula (4) .
20 [00881
In the compound represented by the general formula (31, R5
represents an alkyl group having 1 to 6 carbon atoms which may be
substituted, a cycloalkyl group having 3 to 6 carbon atoms which
may be substituted, an aryl group which may be substituted, an
25 arylalkyl qroup .Ihich may be substituted, a heteroaryl group kihich~~
may be substituted or a heLeroarylalk>-l qroup which may be
substituted.
[00891
In R5, examples of the substituent in the alkyl group having 1
to 6 carbon atoms which may be substituted, the cycloalkyl group
havlng 3 to 6 carbon atoms r.rhich may be substituted, the arylalkyl
5 group which may be substituted, the heteroarylalkyl group which
may be substituted, the aryl group r,ihich may be substituted or the
heteroarylgrouprihichmaybe substitutedinclude alkylgroups such
as a methyl group, an ethyl group, a propyl group, an isopropyl
group, a butyl group, an isobutyl group, a sec-butyl group and the
10 like; cycloalkyl groups such as a cyclopropyl group, a cyclobutyl
group, a cyclopentyl group, a cyclohexyl group'and the like;
halogen-substituted alkyl groups such as atrifluoromethylgroup,
a difluoromethyl group, a brornodifluoromethyl group, a
trifluoroethyl group and the like; alkoxy groups such as a methoxy
15 group, an ethoxyyroup, a propoxy group, an isopropoxy group, a
butoxy group, an isobutoxy group, a sec-butoxy group and the like;
cycloalkoxy groups such as a cyclopropoxy group, a cyclobutoxy
group, a cyclopentyloxy group, a cyclohexyloxy group and the like;
halogen-substituted alkoxy groups such as atrifluoromethoxy group,
20 a difluoromethoxy group, a trifluoroethoxy group and the like;
alkoxycarbonyl groups such as a methoxycarbonyl group, an
ethoxycarbonyl group, a propoxycarbonyl group, an
isopropoxycarbonyl group, a butoxycarbonyl group, an
isobutoxycarbonyl group, a see-butoxycarbonyl group and the like;
25 cycloalkoxycarbonyl groups such as a cyclopropoxycarbonyl group,
a cyclobutoxycarbonyl group, a cyclspsntyloxycarbonyl group, a
cyclohexyloxycarbony1 group zc? the l'!co; zvl:xycarbonyl groups
such as aphenoxycarbonylgroup and the like; alkylthio groups such
as a methylthio group, an ethylthio group, a propylthio group, a
butylthio group andthe like; halogen-substituted alkylthio groups
such as a trifluoromethylthio group, a difluorornethylthi~o group,
5 atrifluoroethylthio group and the like; alkylsulfinylgroups such
as a methanesulfinyl group, an ethanesulfinyl group, a
propanesulfinyl group, a butanesulfinyl group and the like;
halogen-substituted alkylsulfinyl groups such as a
trifluoromethanesulfinyl group, a difluoromethanesulfinyl group,
10 atrifluoroethanesulfinylgroup andthe like; alkylsulfonylgroups
such as a methanesulfonyl group, an ethanesulfonyl group, a
propanesulfonyl group, a butanesulfonyl group and the like;
halogen-substituted alkylsulfonyl groups such as a
trifluoromethanesulfonyl group, a difluoromethanesulfonyl group,
15 atrifluoroethanesulfonylgroup and the like; alkylcarbonylgroups
such as a methylcarbonyl group, an ethylcarbonyl group, a
propylcarbonyl group, an isopropylcarbonyl group and the like;
cycloalkylcarbonyl groups such as a cyclopropylcarbonyl group, a
cyclobutylcarbonyl group, a cyclopropylcarbonyl group, a
20 cyclopentylcarbonyl group, a cyclohexylcarbonyl group and the
like; arylcarbonyl groups such as a benzoyl group and the like;
alkylcarbonyloxy groups such as a methylcarbonyloxy group, an
ethylcarbonyloxy group, a propylcarbonyloxy group, an
isopropylcarbonyloxy group and the like; cycloalkylcarbonyloxy
25 groups such as a cyclopropylcarbonyloxy group, a
cyclobutylcarbonyloxy, group, 2 cycloprntylcarbonyloxy group, a
cyclohexylcarbony-loxy 5ral;p 2x2 tks Ii!rs; zr~lcarbonyloxy groups
such as a benzoyloxy group and the like; and halogen atoms such
as chlorine, fluor~ne, bromine, iodine and the like. The number
of substituents on the aryl group or the heteroaryl group is not
restricted. Furthermore, when two or more parts of the aryl group
5 or heteroaryl group are substituted, the substituents may be the
same or different. There is no restriction in this regard.
[0090]
The alkyl group having 1 to 6 carbon atoms in R5 of the general
formula (3) is the same as those described in Rl of the general
10 formula (1).
[0091]
The cycloalkyl group having 3 to 6 carbon atoms in R5 of the
general formula (3) is the same as those described in R1 of the
general formula (1) .
15 [0092]
The aryl group in R5 of the general formula (3) is the same as
those described in R2 of the general formula (1).
100931
In the arylalkyl group in R5 of the general formula (3), the aryl
20 portion thereof is the same as the aryl group described in R2 of
the general formula (I), while the alkylportionthereof represents
an alkyl group having 1 to 4 carbon atoms.
[0094]
Examples of the heteroaryl group in R5 of the general formula
25 (3) ir~clude nitrogen-contzining heterocyclic^ groups s ~ ~ cash a
pyridyl group, a pyrimidyl Grzlp, 2 pyrazolyl group, a pyrazinyl
group, a pyridazy~yl~ xcuc,? n i!?rl?zolrrl qroup, an indolyl group,
a qulnolyl group, a quinoxalyl group, a benzimidazolyl group and
the llke; sulfur-containing heterocyclic groups such as a
tetrahydrothlenyl group, a thienyl group, a thiopyranyl group, a
benzothienyl group and the llke; oxygen-containing heterocyclic
5 groups such as a tetrahydrofuranyl group, a furanyl group, a
pyranyl group, a dioxanyl group, a 2,3-dihydrobenzo [ l , 4 ] dioxynyl
group, a benzofuranyl group and the like; and heterocyclic groups
containing two or more hetero atoms such as an oxazolyl group, an
isoxazolyl group, a thiazolyl group, an isothiazolyl group, a
10 benzoxazolyl group, a benzoisoxazolyl group, a benzothiazolyl
group, a benzoisothiazolyl group and the like.
[0095]
In the heteroarylalkyl group in R5 of the general formula (3),
the heteroaryl portion thereof is the same as the heteroaryl group
15 in R5 of the general formula ( 3 ) , while the alkyl portion thereof
represents an alkyl group having 1 to 4 carbon atoms.
In the compound represented by the general formula (31, X
represents a leaving group.
[0096]
20 Examples of the leaving group represented by X of the general
formula (3) include halogen atoms such as fluorine, chlorine,
bromine, iodine and the like; alkoxygroups suchas amethoxygroup,
an ethoxy group and the like; aryloxy groups such as a phenoxy group,
a 4-nitrophenyl group and the like; acyloxy groups such as an
n 7 La acetyloxy group, a benzoyloxy group and the like; ~ ~
alkoxycarbonyloxy groups s:>,zh as a methoxycarbonyloxy group,' an
ethoxycarbonylox>- grz-:;, sc lsz>~:t:~lzxycarbonyloxy group and the
like; arylcarbonyloxy groups such as a phenylcarbonyloxy group and
the like; alkylthio groups such as a methylthio group and the like;
a 2,5-dioxopyrrolidinyloxy group, a benzotriazolyloxy group, an
imirla7olyl group and the like.
5 [00971
In the compound represented by the general formula (4), R1, R2,
R3 and R4 are the same as those described in the genera% formula
(I), while R5 is the same as those described in the general formula
(3).
' 10 [0098]
The amount of the compound represented by the general formula
(3) used is not particularly limited as long as it is equal to or
not less than the equivalent of the compound represented by the
general formula ( Z ) , but it is preferably from not less than 1
15 equivalent to not more than 3 equivalents from the economic
perspectives.
[00991
When the compound represented by the general formula (2) forms
a salt with an acid, or when an acid is generated r.~hilet he compound
20 represented by the general formula (2) is reacted with the compound
represented by the general formula (3), a base can be used.
[01001
Examples of the base to be used include inorganic bases such as
sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate,
25 potassium hydrogen carbonate, svcliuii~ carbonate, potassium
carbonate and the l i k s ; ccd organic bases such as pyridine,
, - -.:--L-.- ..- collidine, picoiize, = i--..l-: .dpyridine, lutidine,
triethylamine, diisopropylamine, diisopropylethylamine,
tributylamine, 1,8-diazabicyclo [5,4,0] -undec-7-ene,
1,4-diazabicyclo[2,2,O]octane, imidazole and the like. These
bases can be used singly, or two or more kinds thereof can be used
5 in combination at an optional ratio.
[OlOl]
The base can be used in an amount of not less than 1 equivalent,
based on the acid when the cornpound'represented by the general
formula (2) forms a salt with an acid. Or, when an acid is generated
10 during the reaction, the base can be used in an amount of not less
than 1 equivalent, based on the acid to be generated. Its upper
limit is preferably not more than 10 equivalents from the economic
perspectives .
[0102]
15 The solvent to be used when the compound represented by the
general formula (2) is reacted with the compound represented by
the general formula ( 3 ) is not particularly limited as long as the
compound represented by the general formula (4) is generated.
Concrete examples of the solvent include halogen solvents such as
20 dichloromethane, chloroform and the like; aromatic solvents such
as benzene, toluene, xylene andthe like; hydrocarbon solvents such
as hexane, heptane and the like; amide solvents such as
dimethylformamide, dimethylacetamide, 1-methyl-2-pyrrolidoneand
the like; urea solvents such as 1,3-dimethyl-2-imidazolidinone,
pyrimid;none
25 1,3-dimethyl-3,4,5,6-tetrahydro-Z( lH)- ~ - r ; - - a?nd- t he h
t"
-i-l ke; ester solvents such as ethyl acetate, butyl acetate,
-;= - n-m - -- nnvl acetate and the like; ether solvents such as diethyl - .- -.
ether, diisopropyl ether, 1,2-dimethoxyethane, tetrahydrofuran,
dioxane and the like; nitrile solvents such as acetonitrile,
propionitrile and the like; alcohol solvents such as isopropanol,
t-hl,tyl alcohol and the like; and water. These solvents can be used
5 singly, or two or more kinds thereof can be used in combination
at an optional ratio.
[0103]
The amount of the solvent used is not particularly limited, but
it is usually from not less than 3 times weight to not more than
10 40 times weight, based on the compound represented by the general
formula (2).
[0104]
The reaction temperature when the compound represented by the
general formula (2) is reacted with the compound represented by
L5 the general formula (3) is not particularly limited as long as the
compound is not decomposed, but it is usually from -10 to 150 degree
centigrade or not more than the boiling point of a solvent.
[0105]
The way of obtaining the compound represented by the general
20 formula (1) is not particularly limited, and commercial products
may be purchased. Or there may be used the compound represented
by the general Formula (1) which is prepared by reacting the
compound represented by the general formula (8) r.rith the compound
represented by the general formula (7) to be obtained with
25 reference to tne Strecker reaction exemplified in Japdr~ese Patei-it--
Laid-open No. 23C.S-Zl593, Tzrrahedron : Asymmetry, Vol. 12, pp. 219
to 228, 2C31, T:-:rnzl cL .k?.eric?n Chemical Society, Vol. 124, No.
34, pp. 10012 t o 10014, 2002 o r t h e l i k e .
[01061
5 I n t h e general formula (8), R2, R3 and R4 a r e t h e same a s those
d e s c r i b e d i n t h e general formula (1)
[01081
0
[01091
10 I n t h e general formula (7), R1 is the same a s t h o s e d e s c r i b e d
i n t h e general formula (1); and Y r e p r e s e n t s a halogen atom such
as f l u o r i n e , c h l o r i n e , bromine, iodine o r t h e l i k e .
[OllO]
In a d d i t i o n , t h e compound r e p r e s e n t e d b y t h e general formula (1)
15 can be p r e p a r e d b y r e a c t i n g t h e compound r e p n e s e n t e d b y t h e general
formula (5) with a deoxidizing agent,
[Olll] ~ -
~~ ~~ ~-~~ .~ ~
The react'c: cT the compound r e p r e s e n t e d by t h e general formula
20 (5) with 2 i e c x i d i z i n a aaent t i i l l be described be1or.r.
I n t h e compound r e p r e s e n t e d by t h e general formula (5), R l , R2,
R3 and R4 are the same as those described in the general formula
(1).
[0112]
Examples of the deoxldlzing agent include halogenating agents
5 such as thlonyl chloride, oxalyl chloride, phosgene, phosphorus
oxychloride, phosphorus trichloride, phosphorus pentachloride,
thionyl bromide, phosphorus tribromide, mesyl chloride, tosyl
chloride and the like; carbodiimide derivatives such as
N,Nf-dicyclohexylcarbodiimide, N,Nf-diisopropylcarbodiimide,
10 1-ethyl-3-(3-dimethy1aminopropyl)carbodiimide hydrochloride and
the like; anhydrides such as acetic anhydride, trifluoroacetic
anhydride and the like; a vilsmeier reagent and the like
The vilsmeier reagent refers to a compound represented by the
15 general formula (3) :..~hichi s prepared from formamide derivatives
such as dimethylformamide or the like and a halogenating agent,
20 In the general formula (3), R6 and R7 each independently
represent an alkyl group having 1 to 3 carbon atoms; and Y
represents a halogen atom.
Tne compour~ci i-epresented by the general form~~l(a9 ) also
contains 2 s~lrde rived from the halogenating agent.
25 ."---.
j U l l 0 ,
The alkyl group having 1 to 3 carbon atoms in R6 and R7 of the
general formula (9) represents a methyl group, an ethyl group, a
propyl group or the llke.
[0117]
5 The halogen atom in Y of the general formula (9) is fluorine,
chlorine, bromine, iodine or the like.
I01181
The usage of the deoxidizing agent is not particularly limited.
Either of a method including adding a substrate to a deoxidizing
10 agent or a method including adding a deoxidizing agent to a
substrate may be used.
[0119]
The usage ofthe deoxidizing agent when it is a vilsmeier reagent
is not particularly limited either. Amethod including previously
15 preparing a vilsmeier reagent in a solvent, and then adding the
compound represented by the general formula (5) thereto, or a
method including introducing the compound represented by the
general formula (5) and a halogenating agent into a solvent
containing formamide derivatives can be performed
20 [01201
The amount of the deoxidizing agent used is not particularly
limited as long as it is not less than 1 equivalent, based on the
compound represented by the general formula (5), but it is usually
from not less than 1 equivalent to not more than 10 equivalents.
25 to1211
-, / -/ ,7.s- c-.-,la .;nr ~f the deoxidizing agent used ~ ~ h eitn is a vilsmeier
rea ---- - - - -- - - -L: . .
,=A.L L3 ..L~=, _ _ _ -d arly llrnlte:! as lclng as the halogenating
agent is used in an'amount of not less than 1 equivalent based on
the compound represented by the general formula ( 5 ) , and the
formamide derivatives are used in an amount of ndt less than a
catalytic amount. The amount ofthe halogenating agent is usually
5 from not less than 1 equivalent to not more than 10 equivalents,
while the amount of the formamide derivatives are usually from not
less than 0.1 equivalent to not more than 10 equivalents based on
the compound represented by the general formula (5). Furthermore,
I the formamide derivatives can also be used as a solvent.
10 [01221
The solvent to be used when the compound represented by the
general formula (5) is converted into the compound represented by
the general formula (1) is not particularly limited as long as it
is an aprotic solvent. Concrete examples thereof include
15 halogenated solvents such as dichloromethane, chloroform and the
like; aromatic solvents such as benzene, toluene, xylene and the
like; hydrocarbon soivents such as hexane, heptane and the like;
amide solvents such as dimethylformamide, dimethylacetamide,
1-methyl-2-pyrrolidone and the like; ether solvents such as
20 diethyl ether, diisopropyl ether, 1,2-dimethoxyethane,
tetrahydnofuran, dioxane and the like; nitrile solvents such as
acetonitrile, propionitrile and the like; urea solvents such as
1,3-dimethyl-2-imidazolidinone, pyri m;d;hone
. .
1.3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -,w;.rr-l- and the
25 Like; and ester solvents such as ethyl acetate, butyl acetatc,
iscprop-yl acetate and the like. The solvents can be used singly,
-- L_..- ,,,, ...,-, solvents can be used in cornbination at an optional
ratio.
[0123]
In the deoxidizing agents to be used for the present invention,
a vilsmeier reagent can be preferably applied.
5 [0124]
The amount of the solvent used is not particularly limited, but
it is usually preferably from 3 to 40 times weight, based on the
creight of the compound represented by the general formula (5).
[0125]
10 The reaction temperature crhen the compound represented by the
general formula (5) is converted into the compound represented by
the general formula (1) is not particularly limited as long as the
reaction proceeds, but it is from not less than -10 degree
centigrade to not more than 150 degree centigrade or not more than
15 the boiling point of a solvent.
Due to such a convenient reaction, the compound represented by
the general formula (1) can be obtained in a high yield. For that
reason, the reaction is useful as a process for industrially
producing the compound represented by the general formula (1).
20 [0126]
In the present invention, the aforementioned compound
represented by the general formula (5) can be obtained by reacting
a compound represented by the following general formula (6) brith
a compound represented by the follo~~ingge neral formula (7) in the
25 presence of water,
-: ..-; j- 25;
A process for producing the compound represented by the general
5 formula (5) will be explained below.
In the general formula (6), R2, R3 and R4 are the same as those
described in the general formula (1).
LO1291
The compound represented by the general formula (6) also
10 contains a salt formed with an inorganic acid or an organic acid.
Examples oithe inorganic acid include hydrochloric acid, sulfuric
acid, phosphoric acid and the like, while examples of the organic
acid include oxalic acid, fumaric acid, maleic acid, formic acid,
acetic acid, methanesulfonic acid and the like.
15 [0130]
Commercial products can be used for the general formula (6). At
this time, a free body or a salt thereof may be used.
[0131]
R1 in the general formula (7) is the same as R1 in the general
20 formula (I), while Y is a halogen atom such as fluorine, chlorine,
br~mine, iodine or the like.
As a process for production of the compound represented by the
general formula ( 5 ) , the compound can be obtained with good
efficiency by reacting the compound represented by the general
formula (6) with the compound represented by the general formula
(7) in the presence of water. The reactlon carried out in the
5 presence of water is a characteristic of the present invention.
Because of this characteristic, the yield of the compound
represented by the general formula (5) is remarkably improved.
[0133]
The amount of the compound represented by the general formula
10 (7) used is not particularly limited as long as it is not less than
1 equivalent, based on the compound represented by the general
formula (6), but it is from not less than 1 equivalent to not more
than 5 equivalents from the economic perspectives.
101341
15 When the compound represented by the general formula (6) is
reacted ~lith the compound represented by the general formula ( 7 ) ,
a base may be used. Examples of the base include inorganic bases
such as sodium hydroxide, potassium hydroxide, sodium hydrogen
carbonate, potassium hydrogen carbonate, sodium carbonate,
20 potassium carbonate and the like; and organic bases such as
pyridine, collidine, picoline, 4-dirnethylaminopyridine, lutidine,
triethylamine, diisopropylamine, diisopropylethylamine,
tributylamine, 1,8-diazabicyclo[5,4,0]-undec-7-ene,
1,4-dizzabicyclo [2,2,0]o ctane and the like. The bases can be used
0-
~ i ) ~ ~ L L ~ L _ Yor, ~ W Gor ziorc kinds thereof can he used-in combination
st mn optional ratio.
- - - -.-- . L " A - - ,
The amount of the base used is not less than 1 equivalent, based
on the compound represented by the general formula ( 6 ) , or it is
not particularly limited as long as it is not less than 2
equivalents when the compound represented by the general formula
5 (6) is a salt. Its upper limit is preferably not more than 10
equivalents from the economic perspectives.
[0136]
The solvent to be used when the compound represented by the
general formula (6) is reacted with the compound represented by
10 che general formula (7) is water or a solvent containing water.
Two or more solvents containing water can be used in combination
at an optional ratio. Concrete examples of the solvent to be mixed
with water include halogenated solvents such as dichloromethane,
chloroformand the like; aromatic solvents such asbenzene, toluene,
15 xylene and the like; hydrocarbon solvents such as hexane, heptane
and the like; amide solvents such as dimethylformamide,
dimethylacetamide, 1-methyl-2-pyrrolidone and the like; urea
solvents such as 1,3-dimethyl-2-imidazolidinone,
p ~ r i m i d ; ~ n n e
1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -ppwi,: ;!: ,,& and the
20 like; ester solvents such as ethyl acetate, butyl acetate,
isopropyl acetate and the like; ether solvents such as diethyl
ether, diisopropyl ether, 1,2-dimethoxyethane, tetrahydrofuran,
dioxane and the like; and nitrile solvents such as acetonitrile,
propionitrile and the like.
25 [ill371
The compound represented by the general formu1.a (7) can be
2- A: _I_ ._.- -L z ~.&. ;- +- h a solvent and added dropwise. The solvent to be used
at this time is not restricted as long as it is not reacted with
the compound represented by the general formula (7). Concrete
examples of the solvent to be dilutedinclude halogenated solvents
such as dichloromethane, chloroform and the like; aromatic
5 solvents such as benzene, toluene, xylene and the like; hydrocarbon
solvents such as hexane, heptane and the like; amide solvents such
as dirnethylformamide, dimethylacetamide, 1-methyl-2-pyrrolidone
and the like; urea solvents suchas 1,3-dimethyl-2-imidazolidinone,
pyrimid.i n.o ne
', 1,3-dimethyl-3,4,5,6-tetrahydro-2( 1H) - p qand t he
10 like; ester solvents such as ethyl acetate, butyl acetate,
isopropyl acetate and the like; ether solvents such as diethyl
ether, diisopropyl ether, l,2-dirneth~x~ethanet,e trahydrofuran,
dioxane and the like; and nitrile solvents such as acetonitrile,
propionitrile and the like.
[0138]
The amount of the solvent used is not particularly limited, but
it is usually preferably from 3 to 40 times weight, based on the
weight of the compound represented by the general formula (6).
[0139]
The reaction temperature is not particularly limited as long as
the compound is not decomposed, but it is usually from not less
than -30 degree centigrade to not more than ,150 degree centigrade
or not more than the boiling point of a solvent.
[Ol40]
" c
Ld As described above, the compound represcntcd by thc general
F- ormala (4), i.e., ethylenediamine derivatives having a
I.. -- = -I -- -- --..- - 2 ted carbzmate group and an acyl group can be effectively
produced.
EXAMPLES
[0141 1
5 The present invention is now illustrated in detail below with
reference to Examples. However, the present inventlon is not
restricted to these Examples.
[0142]
Hereinafter, tetrahydrofuran is referred to as THE; diisopropyl
10 ether as IPE; dimethylformamide as DME; and isopropyl alcohol as
IPA.
Example 1
Synthesis of N-(2,2,2-trifluoroethoxycarbonyl)-L-valinamide
(hereinafter referred to as the compound (I))
15 [01431
9 HCI
[0144]
To 25.0 g of valinamide hydrochloride was added 325 ml of water,
andthe pH ofthe reaction solutionbecame 8 byadding of a 8 weight%
20 aqueous sodium hydroxide solution. 35 ml of dioxane containing
31.94 g of 2,2,2-trifluoroethoxycarbonyl chloride and a 8 weight %
aqueous sorli~lm hydroxide d solution were added dr_opxl~.liset o t.hc-~
solution at the same time while maintaining the pH at 8 + 0.5 at
room temperature. After the completion of dropwise addition, the
25 solution was stirred for 2 hours and then the precipitate was
filtered and vacuum dried. The obtained compound of a white solid
was the title compound.
Quantity: 37.80 g (Yield: 95%)
'H NMR (OMSO-d6)
5 60.84 (3H,d, J=6.83Hz), 0.86 (3H,d, J=6.83Hz), 1.98 (lH,m), 3.78 (lH, dd
[0145]
Comparative Example 1
10 synthesis OF N-(2,2,2-trifluoroethoxycarbonyl)-L-valinamide
without water
To 30 ml of a THE solution containing.3.0 g of valinamide
hydrochloride r.ras added 5.25 ml of pyridine, and then 5 ml of THF
containing 3.83 g o f 2,2,2-trifluoroethoxycarbonyl chloride was
15 added dropwise to the solution . The resulting mixture was stirred
at room temperature for 3 hours, and then water and ethyl acetate
were added to the mixture ,and carried out liquid separation. The
organic layer was washed with 1N hydrochloric acid, a saturated
sodium hydrogen carbonate solution and a saturated sodium chloride
20 solution, and then dried over sodium sulfate. After removing
sodium sulfate, IPE was added and the resulting mixture was stirred.
The obtained white precipitate was the compound (I), while the
yield was 47% (quantity: 2.25 g) . Even when the same reaction was
carried out usingtriethylamine instead of pyridine, the yield was
25 30%. From these^ reaction results, it was determined that, in^ -~
Example 1 carried out with an aqueous solvent, the reaction yield
was remarkably iii~proosd.
Example 2
Synthesis of
N-(2,2,2-trifluoroethoxycarbonyl)-L-valinonitrile (hereinafter
5 referred to as the compound (11))
(01471
[0148]
To 350 ml of toluene were added 35.0 g of the compound (I) and
10 35 ml of DMF, and the resulting mixture was. stirred at room
temperature. 35 mlof toluene containing 22.01 g of oxalylchloride
was added dropwise to the suspension with care. The solution was
stirred at the same temperature for 2 hours, and then 350 ml of
water was added to the mixture, and carried out liquid separation.
15 Further, the separated organic layer was washed with 350 ml of water,
and then the solvent was distilledoff under reducedpressure. Next,
by distillation, the fraction of distillate was isolated at 116
to 122 degree centigrade in 0.3 rnmHg. The obtained colorless and
transparent oily substance was the title compound.
20 Quantity: 29.89 g (Yield: 92%)
'H NMR (CDC13)
61.10 (3H,d,J =6.83Hz),1 .12 (3H,d,J =6.83Hz), 2.09( lH,s ept,J =6.83Hz
) ,4.4~ 4.6(3H,m)5,. 31( lH,brd).
[0149]
25 Eiiampls 3
Synthesis of Compound (11) by Process for Production of
Vilsmeier in Advance
To 5 ml of toluene containing 1 ml of DMF was added dropwise 5
ml of a toluene solution containing 433 p1 of oxalyl chloride at
5 room temperature. The resulting solution was stirred for 30
minutes, andtheni.O g ofthe compound (I) wasintroducedthereinto
and reacted for 3 hours. The organic layer was washed with water,
and then purifiedby silica gelchromatographyto obtain a compound
(11).
10 Quantity: 0.92 g (Yield: > 99%)
[0150]
Example 4
Synthesis of Compound (11) with Ethyl Acetate as Solvent
The synthesis was carried out in the same manner as in Example
15 2, except that 5.0 g of the compound (I) was used, a solvent was
changed from toluene to ethyl acetate, and a purification method
was changed from distillation to column chromatography. As a
result, a compound (11) could be obtained.
Quantity: 4.45 g (Yield: 96%)
20 [01511
Example 5
Synthesis of
(2s)- 3-Plethyl-~'- (2,2,2-trifluoroethoxycarbonyl)- butane-i,2-dia
mine hydrochloride (hereinafter referred to as the compound (111) )
25 (1)
[01521
[ O l 531
To 180 m l of IPA were s u c c e s s i v e l y added 26.8 g of acetic acid,
2 . 0 g of 5% palladium carbon ( w a t e r : 49.5%, a product of N . E. Chem. )
5 and 1 4 . 1 g of ammonium formate, and t h e r e s u l t i n g s o l u t i o n was
s u f f i c i e n t l y s t i r r e d . 10 m l of IPA c o n t a i n i n g 10.0 g of t h e
compound (11) was added dropwise t o t h e s o l u t i o n a t room
temperature, and then the s o l u t i o n was s t i r r e d a t t h e s a m e
t e m p e r a t u r e f o r 2.5 hours. The c a t a l y s t tias removed by f i l t e r i n g
10 and then t h e s o l v e n t was d i s t i l l e d o f f under reduced p r e s s u r e . To
t h e r e s i d u e were added water and e t h y l a c e t a t e . Subsequently,
potassiumcarbonatevras a d d e d u n t i l t h e p H o f t h e w a t e r l a y e r b e c a r n e
about 10 t o c a r r y out l i q u i d s e p a r a t i o n . To t h e s e p a r a t e d o r g a n i c
l a y e r was added sodium s u l f a t e , and t h e organic l a y e r was d r i e d
15 and f i l t e r e d . T h e r e a f t e r , a 4N hydrogen c h l o r i d e - e t h y l a c e t a t e
s o l u t i o n was added t o the s o l u t i o n . When the s o l u t i o n was
c o n c e n t r a t e d under reduced p r e s s u r e , a white s o l i d was
p r e c i p i t a t e d and t h e p r e c i p i t a t e was f i l t e r e d t o o b t a i n t h e t i t l e
compound.
20 Q u a n t i t y : 1 0 . 5 g ( Y i e l d : 89%)
'H NMR (DMSO-ds)
60.83 (3H,d, J=6.83Hz), 0.85 (3H,d, J=6.83Hz), 1.77 ( I H , sept, J=6.83Hz
) , 2 . ' / 4 (IH, dd, J=9.76,13.1782), 2.93 (lH,dd, J=3.42,13.17Hz) ,-3.54 (1 ~~
H,m) , 4 . 5 5 ( l H , m ) , 4.73 ( l H , m ) , 7.67 (lH,d, J=9.27Hz), 8.02 (3H, b r s ) .
25 [Oi54j
Example 6
Synthesis of Compound (111) (2)
In an autoclave, SO ml of IPA containing 3.30 g of the compound
(11) , 9.0 g of acetic acld and 0.6 g of 5% pa11adi1lm carbon (water:
49.5%, a product of N.E. Chem) was pressurized with hydrogen gas
to 2.1 MPa, and then the reaction was carried out at room
temperature. After the reactlon was carried out for 5 hours, and
then the catalyst was removed and the resulting solution was
concentrated under reduced pressure. At this point of time, when
a free body of the compound (111) was quantitatively analyzed with
high performance liquid chromatography, the reaction yieldwas 95%
Tothe residue were added water and ethyl acetate, and subsequently
the pH of the water layer was set to 10.7 by adding of a 8 v~eight %
aqueous sodium hydroxide solution to carry out liquid separation.
The organic layer was dried over sodium sulfate and filtered, and
then 10 ml of a 4N hydrogen chloride-ethyl acetate solution was
added to the solution. When the solution was concentrated under
reduced pressure, a white solid was precipitated and the
precipitate was filtered to obtain the title compound.
Quantity: 3.60 g (Yield: 92%)
[0155]
Example 7.
Synthesis of Compound (111) (3)
The reaction was carried out in the same manner as in Example
6, except that methanol was used instead of IPA and a catalytic
amount was 5 times. A free body of the compound (111) was obtained
wich rhe reaction yield of 93%.
[01561
Example 8
Synthesis of Compound (111) ( 4 )
The rcactlon was carried ont i n the same manner as i n Example
5 7 , except t h a t ethanol was used Instead of methanol. A f r e e body
of the compound (111) was obtained with the reaction yield of 91%.
Reference Example 1
The r e d u c t i o n o f t h e compound (11) was c a r r i e d o u t w i t h reference
to Non-patent Document 2. In an autoclave, 30 m l of s a t u r a t e d
ammonia ethanol containing 0.6 g of the compound (11) and 0 . 6 g
of Raney nickel (a product of Wako Pure Chemical I n d u s t r i e s , Ltd.)
i 15 was pressurizedi,rithhydrogen gas to 0.35MPa, and then the reaction
b~as carriedoutatroomtemperature. A f t e r t h e reactionr,ras c a r r i e d
out for 5 hours, and then the c a t a l y s t was f i l t e r e d and the solvent
was d i s t i l l e d off under reduced pressure. When I P E was added and
the p r e c i p i t a t e Was f i l t e r e d , the obtained compound was not a f r e e
20 body of the intended compound ( I I I ) , but
~~ ~
~ ~
N-(aminocarbony1)-L-valinonitrile ( h e r e i n a f t e r r e f e r r e d t o as the
impurity ( I ) ) . As described above, it was determined t h a t t h e
intendedcompound couldnot be obtainedbythe conventional method.
Quantity of impurity (I): 0.16 g (Yield: 42%)
'H NMR ( DMSO-ds)
60.95( 3H,d,J =6.83Hz),0 .98 (3H,d,J =6.83Hz),1 .94 (lH,m),4 .43 (lH,m)
, 5.78 (2H, s) ,6.75 (lH, brs) .
5 [01591
Example 9
Synthesis
(2~)-3-~eth~l-~~-toluo~l-~~-(2,2,2-trifluoroethoxycarbonyl)-but
ane-l,2-diamine (hereinafter referred to as the compound (IV)) (1)
[0161]
To 25 ml of water containing 1.91 g of sodium hydrogen carbonate
were added 20 ml OF ethyl acetate and 2.0 g of the compound (111) ,
15 and the resulting mixture was stirred. 1.40 g of toluic acid
chloride was added dropwise to the solution. The solution was
stirred at room temperature for 2.5 hours, and then liquid
separation was carried out. To the organic layer was added sodium
sulfate and the organic layer was dried and filtered. Thereafter,
20 the filtrate bras concentrated under reduced pressure. 30 ml of
IPE was further addedtothe redsidue, and the precipitatewas fully
washed and then filtered. The obtained white solid was the title
compound.
Quantity: 2.33 g (Yield: 89%)
25 LO1621
Example 10
Synthesis of Compound (IV) (2)
To a mixed solutlon of 20 ml of ethyl acetate and 30 ml of water
added 2.0 g of the compound (111), and then the pH $./as set to
5 8 by addlng of a 8 weight % aqueous sodium hydroxide solution.
Subsequently, an ethyl acetate solutlon contaming 1.4 g of toluxc
acid chloride and a 8 weight % aqueous sodium, hydroxide solution
were added dropwise to the mixture while maintaining the pH at 7.5
to 8.5. After the completion of the reaction, liquid separation
,
10- was carried out, and the organic layer was driedoversodiumsulfate.
Sodium sulfate was removed and then the solvent was distilled off
under reduced pressure. Subsequently, IPE was added and the
prec~pitate was filtered. The obtained white solid was the title
compound.
15 Quantity: 2.19 g (Yield: 84%)
[0163]
Example 11
Synthesis of
(2~)-3-~eth~i-~'-(l-meth~l-3-trifluorometh~i-l~-~~razole-4-carb
20 onyl) -N2 - (2,2,2-trifluoroethoxycarbonyl-)b utane-l,2-diamine
[01641
[0165] ~ ~ ~ ~.~ ~~~
The reaction was carried out in the same manner as in Example
25 9, except that 1.3 g of the cornpoiifid (111) was used, and
l-methyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl chloride was
used ~nstead of toluic acid chloride.
Yield of white solid: 1.24 g (92%)
NMR (CDC13)
5 60.98( 3H,d,J =G.8 3Hz),1 .00( 3H,d,J =G.8 3Hz),1 .85( lH,m),3 .53( 2H,m)
3.66( lH,m),3 .95( 3H,s ), 4.42( 2H,m),5 .13( lH,b rd) ,6.30( lH,brs),7 .
86(1H,s) .
[0166]
Example 12
I
10 Synthesis of
(2s) -3-methyl-N1- (2,4-dichlorobenzoyl) -N'- (2,2,2-trifluoroethox
The reaction was carried out in the same manner as in Example
9, except that 0.5 g of the compound (111) was used, and
2,4-dichlorobenzoyl chloride was used instead of toluic acid
chloride.
20 Yield of white solid: 0.64 g (96%)
'H NMR (CDC13)
60.99(3H,d,J =6.8 3Hz),l.O1(3H,d,J =6.83Hz),1 .88 (lH,m),3 .53 (lH,m)
3.65 (lH,m), 3.68 (lH,m), 4.43 (2H,m) ,5.16 ilii,d, J=8.78Hz), 6:-50 (-lH,
brs) ,7.30( lH,dd,J =1.95,8.29Hz),7 .41( lH,d,J =1.95Hz), 7.55( lH,d,J
25 =8.23Hz) .
[0169]
Example 13
Synthesis of N-(2,2,2-trifluoroethoxycarbonyl)-L-1eucinamide
(herpinafter referred to as the compound (V))
5 [0170]
HCI
[0171]
The reaction was carried out in the same manner as in Example
1, except that leucinamide hydrochloride was uskd instead of
10 valinamide hydrochloride, and 5.0 g of leucinamide hydrochloride
was used.
Quantity of white solid: 7.0 g (Yield: 91%)
'H NMR (DMSO-d6)
60.85 (3H,d, J=6.34Hz) ,0.87 (3H,d, J=6.83Hz), 1.47 (2H,rn), 1.59 (lH,m)
15 ,3.96(1H,m), 4.69(2H,m),6.98(1H,s),7.36(1H,s),7.74(1H,dJ,= 8.29H
z) .
(01721
Example 14
Synthesis of
20 N-(2,2,2-trifluoroethoxycarbonyl)-L-leucinonitrile (hereinafter
referred to as the compound (VI))
(01741
The reaction was carrled out In the same manner as in Example
2, except that the compound (V) was used instead of the compound
5 (I), and 5.0 g of the compound (V) bras used. At that time,
purification was carrled out not by distillation, but by column
chromatography.
Quantity of yellow oily substance: 4.41 g (95%)
1 H NMR(CDCl3)
10 60.99 (6H, d, J=6.34Hz), 1.7-1.9 (3H,m), 4.47 (lH,m), 4.53 (lH,m), 4.62 (
lH,m) ,5.31 (lH, brd) .
LO1751
Example 15
Synthesis of
15 (2s)- 4-methyl-~'- (2,2,2-trif1~0r0ethox~carbon~-lp)en tane-l,2-di
amine hydrochloride (hereinafter referred to as the compound
(VII) )
The react-ion was carried out in the same manner as in Example
5, except that the compound (VI) was used instead of the compound
(111, and 2.5 q of the compound (VI) xias used.
Quantity of white solid: 2.32 g (Yield: 79%)
'H NMR (DMSO-ds)
,l. 56 (lH,m) ,2.73 ( lH,dd,J =8.78,12.69Hz),2 .82 (l~,dd~,= 4.39,12.69
5 Hz), 3.76( lH,m),4 .57 (lH,m),4 .69 (lH,m),7 .67 (IH,d ,J =8.78H~)8,. 06(
3 ~b;rs ) .
Example 16
Synthesis of
H * HCI H 0
[0180]
15 The reaction was carried out in the same manner as in Example
9, except that the compound (VII) was used instead of the compound
(111), and 0.5 g of the compound (VII) was used.
Quantity of white sol~d: 0.56 g (Yield: 87%)
'H NMR (CDC1,)
20 60.94( 3H,d,J =6.34Hz),0 .95(3H,d,J =6.34Hz),1 .38 (lH,m), 1.43 (1H,m)
Synthesis of
(2~)-4-meth~l-~~-(l-meth~l-3-trifluorometh~l-1~-~~razole-4-carb
onyl)-~~-(2,2,2-trifluoroethoxycarbonyl)-pentane-l,2-diamine
LO1831
The reaction was carried out in the same manner as in Example
9, except that the compound (VII) was used instead of the compound
( I I I ) , l-methyl-3-trifluoromethyl-lH-pyrazole-4-carbonyl
10 chloride was used instead of toluic acid chloride, and 0.3 g of
the compound (VII) was used.
Yield of white solid: 0.36 g (Yield: 80%)
1 H NMR(CDCl3)
60.93 (3H,d, J=6.34Hz), 0.95 (3H, d, J=6.34Hz),1 .38 (2H,m),1 .68 (lH,m)
15 ,3.45( lH,m),3 .54 (lH,m),3 .89 (lH,m), 3.96( 3H,s ) ,4.43( 2H,m),5 .05(1
H,d, J=8.78Hz), 6.34 (lH, brs) ,7.87 (lH, s) .
[0184]
Example 18
Synthesis of
20 (2s)- 4-~ethyl-N'- (2,4-dichlorobenzoyl)- NZ- (2,2,2-trifluoroethox
I
. HCI H 0 CI
[0186]
The reaction was carried out in the same manner as in Example
9, except that the compound (VII) was used instead of the compound
(111), 2,4-dichlorobenzoyl chloride was used instead of tolulc
5 acid chloride, and 0.2 g of the compound (VII) was used.
Quantity of white solid: 0.29 g (Yield: 97%)
'H NMR (CDCl3)
60.94 (3H, d, J=5.37Hz), 0.96 (3H, d, J=6.34Hz),1 .42 (2H,m],1 .71 (lH,m)
,3.54( 2H,m),3 .93( lH,m),4 .42( 2H,m),5 .08( lH,d ,J =8.30Hz), 6.57 (lH,
10 brs) ,7.30 (lH,d d, J=1,95,8,29Hz),7 .41( lH,d,J =1.95Hz),7 .56( lH,d,J
=8.29Hz) .
[0187]
Example 19
Synthesis of
15 N-(2,2,2-trifluoroethoxycarbonyl)-L-isoleucinamide (hereinafter
referred to as the compound (VIII))
[0188]
a HCI
[0189]
20 The reaction was carried out in the same manner as in Example
1, except that isoleucinamide hydrochloride was used instead of
valinamide hydrochloride, and 5.0 g of isoleucinamide
hydrochloride was used.
Quantity of white solid: 7.31 g (Yield: 95%)
25 'H NMR ( DMSO-ds)
60.82 (6H,m),1 .13( lH,m),1 .41(1H,m), 1.71( lH,m), 3.81( lH,t , J=8.29H
2) ,4. 64 (2H,
q, J=9.27Hz), 7.05 (lH,s), 7.39(1H, s), 7.65 (lH,d, J=8,29Hz) .
[01901
5 Example 20
Synthesis of
(hereinafter referred to as the compound (IX))
[0192]
The reaction was carried out in the same manner as in Example
2, except that the compound (VIII) was used instead of the compound
(I), and 5.0 g of the compound (VIII) was used. At that time,
15 purification was carried out not by distillation, but by column
chromatography.
Quantity of colorless oily substance: 4.53 g (Yield: 97%)
'H NMR (CDCl,)
60.98 (3H,t , J=7.32Hz),1 .10 (3H,d,J =6.83H~)1,. 34 (lH,m),1 .59 (lH,m)
20 ,l. %3(lH,m), 4.48 (lH,m), 4.53(1H,m), 4.59(1H,m), 5.35(1H,brd) .
[0193]
Example 21
Synthesis of
(2S,3 s)- 3-methyl-N2- (2,2,2-trifluoroethoxycarb~ny-lp)e ntane-l,2
25 -didmine hydrochloride (hereinafter referred to as the compound
K v
H HCI
[01951
5 The reaction was carried out in the same manner as in Example
5, except that the compound (IX) was used instead of the compound
(11) , and 2.5 g of the compound (IX) was used.
~uantity of light peach solid: 2.56 g (Yield: 92%)
'H NMR (DMSO-ds)
10 60.84(6H,m), 1.11(1H,rn), 1.36(1H,m), 1.53(1H,m) ,2.75(1H,dd, Jz10.2
5,12.69Hz), 2 .92 (lH,dd,J =2.93,12.69Hz), 3.60 (lH,m)( 4.55( lH,m),4 .
72 (lH,m),7 .73 (1~,d5,= 8.78~z),8 .10( 3H,brs).
[0196]
Example 22
15 Synthesis of
(25'35) -3-methyl-~1-toluoyl-~(22-, 2,2-trifluoroethoxycarbonyl)-
pentane-1,2-diamine
[0197]
. HCI 0
20 [01981
The reaction was carried out in the same manner as in Example
9, except that the compound (X) was used instead of the compound
(111) , and 0.5 g of the compound (X) was used.
Quantity of white solid: 0.56 g (Yield: 87%)
Example 23
"I) Me
Flc~oKN NH2 A
0 HCI H
0 CF3
[02011
10 The reaction was carried out in the same manner as in Example
9, except that the compound (X) was used instead of the compound
(III), l-methyl-3~trifluoromethyl-1H-pyrazole-4-carbonyl
chlorlde was used instead of toluic acld chloride, and 0.3 g of
the compound (X) was used.
15 Quantity of white solid: 0.45 g (Yield: > 99%)
'11 NMR (CDC13)
60.94 (3H, t, J=7.32Hz), 0.97 (3H,d, J=6.83Hz), 1.19 (lH,m) ,I. 5-1.6(2H
,m) ,3.53 (2H,m), 3.72 (1H,rn), 3.95 (311, s) ,4.43 (2H,m), 5.16 (1H,brd), 6
.30 (1H, brs) ,7.85 (1H, s) .
20 [0202]
Example 24
Synthesis of
~ ~ - - - ~~
(2s. 3s) -3-methyl-N'- (2,4-dichlorobenzoyl) -N2- (2,2,2-trifluoroet
The reaction was carried out in the same manner as in Example
9, except that the compound (X) was used instead of the compound
5 (III), 2,4-dichlorobenzoyl chloride was used instead of toluic
acid chloride, and 0.2 g of the compound (X) and
2,4-dichlorobenzoyl chloride was used.
Quantity of white solid: 0.27 g (Yield: 90%)
'H NMR (CDC13)
10 60. 95 (3H, t, J=7.32Hz), 0.99 (3H, d, J=6.83Hz), 1.22 (1H,m), 1.55 (1H,m)
, 1.67( 1H,m),3 .52 (lH,m), 3.64( 1H,m), 3.76 (1H,m),4 .42( 2H,m),5 .21 (1
H,d ,J =8.78Hz),6 .50( lH,b rs) ,7.29( IN,d d,J =1.95,8.29Hz),7 .41 (1H,d
, J=1.95Hz),7 .54( lH,d,J =8.29Hz). '
[0205]
15 Example 25
Synthesis of
N-(2,2,2-trifluoroethoxycarbonyl)-L-pheny1a1aninamide
(hereinafter referred to as the compound (XI))
[02061
20 O HCI
The reaction \.!as carried out in the same manner as in Example
1, except that phenylalaninamide hydrochloride was used instead
of valinamide hydrochloride, and 5.0 g of phenylalaninamide
hydrochloride was used.
5 White solld: 6.67 g Quantity: 6.76 g (Yleld: 93%)
'H NMR ( DMSO-ds)
10 Example 26
Synthesis of
N-(2,2,2-trifluoroethoxycarbonyl)-L-phenylalaninonitrile
(hereinafter referred to as the compound (XII))
[0209]
[0210]
The reaction rJas carried out in the same manner as in Example
2, except that the compound (XI) was used instead of the compound
(I), and 5.0 g of the compound (XI) bras used. At that time,
20 purification was carried out not by distillation, but by column
chromatography.
White solid: 3.97 g (Yield: 85%)
~.
'H NMR (CDC13)
63.13(2H,m) ,4.49(2H,m), 4.86(1H,m) ,5.29(1H,brd) ,7.28 (23,z.), 7.37
25 (3H,m).
Example 25
Synthesis of
(2s)- N2- (2,2,2-trifluoroethoxycarbonyl)- 3-phenyl-propane-l,2-di
5 amlne hydrochloride (hereinafter referred to as the compound
[02131
10 The reaction was carried out in the same manner as in Example
5, except that the compound (XII) was used instead of the compound
(II), and 2.0 g of the compound (XII) was used.
Quantity of white solid: 2.04 g (Yleld: 88%)
IH NMR ( DMSO-d6)
15 62.72 (lH, m) ,2.85 (3H,m), 3.91 (lH,m) ,4.56 (2H,m), 7.21 (3H,m) ,7.30 (2
H,m) ,7.80 (lH, d, J=8.78Hz), 8.09 (3H,brs) .
[0214]
Example 28
Synthesis of
20 (2.5)- ~ ' - t o l u o ~ l(~2,~2-,2 -trifl~0r0ethoxycarbonyl-)3 -phenyl-pro
0 :"" 0
F 3 c n o k i NHz - F3cnoAN H
HCI 0
The reaction was carried out in the same manner as in Example
9, except that the compound (XIII) was used instead of the compound
5 (III), and 0.3 g of the compound (XIII) was used.
White solid: 0.35 g (Yield: 93%)
'H NMR (CDC13)
62.39(3H, s) ,2.83 ( lH,dd,J =7.81,14.15Hz),3 .00 (lH,dd,J ~6.83~14.15
Hz),3 .53 (1H,m), 3.59( lH,m),4 .11( lH,m), 4.40( ZH,m),5 .63 (lH,d ,J =7.
10 81Hz),6 .52( lH,brs), 7.24( 5H,m),7 .33( 2H,m),7 .62( 2H,d ,J =7.81Hz).
[0217]
Example 29
Synthesis of
(2s)- N'- (l-methyl-3-trifluoromethyl-lH-pyrazole-4-carbonyl-)N 2-
[0219]
The reaction was carried out in the same manner as in Example
~ ~
~ ~~~
20 9, except that the compound (XIII) was used insteadof the compound-
(III), l-methyl-3-trifluoromethyl-lH-pyraz01e-i-~~~~~~~>'~
. " - - --
chloride was used instead of toluic acid chioricis, s ~ zv . 3~
t h e compound ( X I I I ) was used.
Quantity of white s o l i d : 0.28 g (Yield: 97%)
'H NMR (CDC13)
62.81 (lH, dd, J=7.81,14.15Hz), 2.97 (1H,dd, J=6.83,14.15Hz) ,3.52 (2H
5 , m ) ,3.96(3H, s) , 4 . 0 3 ( l H , m ) , 4 . 4 1 (2H,m) ,5.50 (lH,d, J=7.81Hz), 6.30 (
l H , b r s ) , 7 . 2 0 (2H,m), 7.24 ( l H , m ) , 7 . 3 3 (2H,m), 7.88 1 , s .
[02201
Example 30
Synthesis of N-(2,2,2-trifluoroethoxycarbonyl)-L-alaninamide
, 10 ( h e r e i n a f t e r r e f e r r e d t o a s t h e compound ( X I V ) )
1
[02211
1 ,
a HCI
[02221
15.0 g o f alaninamide hydrochloride was added t o 250 m l of water
15 c o n t a i n i n g 25.29 g of sodium hydrogen carbonate and 300 m l of e t h y l
a c e t a t e , and the r e s u l t i n g mixture was s t i r r e d u n t i l it became
uniform. An e t h y l a c e t a t e s o l u t i o n c o n t a i n i n g 23.48 g of
2,2,2-trifluoroethoxycarbonyl c h l o r i d e was added dropwise t o t h e
s o l u t i o n a t room t e m p e r a t u r e o v e r 30 minutes. The s o l u t i o n w a s
20 s t i r r e d a t t h e same temperature f o r 2 hours, and then l i q u i d
s e p a r a t i o n was c a r r i e d o u t . The o r g a n i c l a y e r \ . ~ ads r i e d o v e r sodium
s u l f a t e and f i l t e r e d , and t h e n t h e s o l v e n t was d i s t i l l e d o f f under
r e d u c e d p r e s s u r e . T o t h e r e s i d u e was addedhexane a n a t h e s o l u t i o n
~
~~~ ~
~ -~
was s t i r r e d . T h e r e a f t e r , t h e p r e c i p i t a t e w a s f i l t e r e d t o o b t a i n
25 t h e t i t l e compound.
Quantity of white solid: 24.61 g (Yield: 95%)
1~ NMR ( DMSO-ds)
61.21 (3H,d,J =7.32Hz),3 .96 (lH,m), 4 .62 (2H,m),6 .98( lH,b rs) ,7.33( 1
Example 31
Synthesis of
N-(2,2,2-trifluoroethoxycarbonyl)-L-a1aninonitrie (hereinafter
referred to as the compound (XV))
[0225]
The reaction was carried out in the same manner as in Example
2, except that the compound (XIV) was used instead of t5e compound
15 (I), and 31.0 g of the compound (XIV) was used. At that time,
purification was carried out not by distillation, but by column
chromatography.
Quantity of white solid: 25.83 g (Yield: 91%)
'H NMR(CDC13)
20 61.61 (3H, d, J=7.32Hz), 4.47 (lH,m) , 4.53 (lH,m) , 4.67 (lH,m), 5.38 (lH,
brd) .
[02261
Example 32
Synthesis of
26 (2s)- N'- (2,2,2-triilu0r0ethoxy~arbonyl-)p ropane-1,2-dianine
hydrochloride (hereinafter referred to as the compound (XVI))
[0227]
0 Me 0 Me U P F~~"T)" ' N 'CN F~C/"O N
,k LI\IH~
H * HCI
5 The reaction was carried out in the same manner as in Example
5, except that the compound (XV) $.!as used instead of the compound
(11) , and 2.0 g of the compound (XV) was used.
Quantity of white solid: 2.05 g (Yield: 85%)
'H NMR ( DMSO-dtj)
10 dl. 12 (3H, t, J=6.83Hz), 2.81 (2H,m), 3.79 (lH,m) , 4.60 (lH,m) , 4.67 (lH,
m) ,7.76 (lH,d, J=8.29Hz), 8.12 (3H, brs) .
[0229]
Examp1.e 33
Synthesis of
15 (2s)- ~~-toluo~l(-2N,~2,-2 -trifl uoroethoxycarbonyl)- propane-l,2-
diamine
[0230]
[0231]
20 The reaction was carried out in the same manner as in Example
9, except that the compound (XVI)~i.!as ~ u. sed instead of the compound
~ -~
~ ~~~
(III), and 0.5 q of the compound (XVI) ?re5 -xed.
Quantity of white solid: 0.56 g (Yield: 84%)
'H NMR (CDC13)
61.26 (3H, d, J=6.83Hz), 2.39 (3H, s) ,3.53( 2H,m),3 .95 (lH,m),4 .41 (2H,
m) ,5.50( lH,b rd,J =7.32Hz),6 .74( lH,b rs) ,7.22 (2H,d,J =7.81Hz),7 .66
Example 34
Synthesis of
The reaction was carried out in the same manner as in Example
9, except that the compound (XVI) was used instead of the compound
15 (111), 1-methyl-3-trifluoromethyl-lH-pyrazole-4-carbonyl
chloride was used instead of toluic acid chloride, and 0.3 g of
the compound (XVI) was used.
Quantity of orange solid: 0.38 g (Yield: 79%)
'H NMR (CDC13)
20 61.24 (3H, d, J=6. 83Hz), 3.50 (2H,m), 3.93 (lH,m), 3.96 (3H, s) ,4.42 (2H,
[0235]
Example 35
Synthesis of N- ( 2 , 2 , 2 - t r i f l u o r o e t ~ I o x ~ - ~ z r b -0L~-~p~ro-l1i)n amide
25 (hereinafter referred to as the compound (XV-2))
To 65 ml of water containing 5.0 g of prolinamide was added
5 dropwise 7 ml of dioxane containing 8.54 g of
2,2,2-trifluoroethoxycarbonyl chloride at room temperature. When
the pH of the reaction solution became 8, dropwise addition of a
8 weight % aqueous sodium hydroxide solution also started at the
same time, and the pH of the reaction solution was maintained at
10 8 + 0.5. After the completion of dropwise addition, the solution
was stirred for 2 hours, and then ethyl acetate was added to the
solution to carry out liquid separation. The organic layer was
dried over sodium sulfate and filtered, and then the filtrate was
put under reduced pressure to remove the solvent. The obtained
15 solid was the title compound.
Quantity of white solid: 8.48 g (Yield: 81%)
'H NMR ( DMSO-ds)
61.82( 3H,m),2 .16 (lH,m), 3 .38 (lH,m), 3.46( 1H,m),4 .13 (lH,m), 4.6-4.
7 (2H,m),6 .99( lH,s ), 7.41( lH,s).
20 [0238]
Example 36
Synthesis of
fJ (2,2,2-trifluoro~thoxycarhony1)-L-prolinonitrile( hereinafter
referred to as the compound (XVI-2))
25 [0239!
[0240]
The reactlon was carried out in the same manner as In Example
2, except that the compound (XV-2) was used instead of the compound
5 (I), and 5.0 g of the compound (XV-2) was used. At that time,
purification was carried out not by distillation, but by column
chromatography.
Quantity of yellow transparent oily substance: 4.13 g (Yield:
89%)
10 'H NMR (CDC13)
62.1-2.3 (4H, m) ,3.46 (lH,m) , 3.63 (lH,m), 4.49 (lH,m) ,4.61(2H,m) .
[0241]
Example 37
Synthesis of
15 ., (2s) -N- (2,2,2-trifluoroethoxycarbonyl) -2- (aminomethyl) -pyrroli
dine hydrochloride (hereinafter referred to as the compound
(XVII))
20 I02431
The reaction was carried out in the same manner as in Example
5, except that the compound (XVI-2) was usedinsteadofthe compound
(2), and 2.0 g of the compound (XVI-2) was used
Quantity of white solid: 1.67 g (Yield: 71%)
1 H NMR ( DMSO-d6)
61.8-2.0(4H,m),2.86(1H,m),2.96(1H,m),3.38(2H,m),~.~~(~H,m),~.~
9 (2H,m), 8.19 (3H, brs)
5 [02441
Example 38
Synthesis of
(2S)-N-(2,2,2-trifluoroethoxycarbonyl)-2-(N-to1uoyl-amin0methy
102461
The reaction was carried out Ln the same manner as in Example
9, except that the compound (XVII) tias used instead of the compound
15 (111) , and 0.5 g of the compound (XVII) was used.
Quantity of wh~te solid: 0.50 g (Yield: 80%)
'H NMR (CDC13)
81.8-2.2( 4H,m),2 .39 (3H,s ), 3.4-3.5( 3H,m),3 .68( lH,m),4 .19( 1H,m),
4.52 (2H,m),7 .23 (2H,d,J =8.29Hz),7 .72( 2H,d,J =8,29Hz),7 .79 (lH,brs
20 ) .
[0247]
Example 39
Synthesis of
(2S)-N-(2,2,2-tr1fluoroethoxycarbonyl)-2{N-(l-methyl-3-trifluo
[0248]
,CH3
&NNH 2 A
F3-C -OAo HCI
The reaction was carried out in the same manner as in Example
5 9, except that the compound (XVII) !.!as used instead of the compound
(III), l-methyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl
chloride was used instead of toluic acid chloride, and 0.3 g of
the compound (XVII) was used.
Quantity of colorless and transparent oil: 0.46 g (Yield: >
10 0.99%)
'H NMR (CDC13)
61.8-2.2 (4H,m), 3.4-3.7 (4H,m), 3.96 (3H, s) ,¶.lo (lH,m) ,4.49 (2H,m),
7.11 (lH,brs), 7.80 (lH, s) .
[0250]
15 Example 40
Synthesis of
(2s) -N- (2,2,2-trifluoroethoxycarbonyl) -2 (N- (2,4-dichlorobenzoy
1)-aminomethyl)-pyrrolidine
LO2511
The reaction was carried out in the same manner as in Example
9, except that the compound (XVII) tias used instead of the compound
( I I I ) , 2,4-dlchlorobenzoyl chloride was used instead of toluic
acld chloride, and 0.3 g of the compound (XVII) was used.
Quantlty of whlte solld: 0.37 g (Yield: 81%)
'H NMR (CDCl3)
5 61.7-2.2 (4H,m) ,3.4-3.8 (4H,m), 4.13 (lH,m), 4.48(2H,m), 7.29(1H,dd,
J=1.95,8.30Hz),7 .34 (lH,brd), 7.42( lH,d ,J =1.95Hz), 7.53( lH,d , J=8.
30Hz) .
[02531
Example 41
10 Synthesis of
N-methyl-N-(2,2,2-tr~fluoroethoxycarbonyl)-L-valinamide
(hereinafter referred to as the compound (XVIII))
[0254]
Me.
H I
* HCI Me
[0255]
To 60 ml of water containing 3.0 g of N-methyl-L-valinamide and
4.54 g of sodium hydrogen carbonate was added dropwise 6 ml of
dioxane containing 3.51 g of 2,2,2-trifluoroethoxycarbonyl
chloride at room temperature over 20 minutes. The resulting
20 solution was stirred for 2 hours, and then ethyl acetate was added
to the solution ,and carried out liquid separation. The obtained
organic layer was dried over sodium sulfate and filtered, and then
L i ~ es olveint was distilled off under rcduccd pressure. The obtained
compound was the title compound.
2.5 Quantity of colorless oily substance: 4.61 g (Yield: > 99%)
'H NMR (CDC13)
inor), 4.09 (lH,d), 4.51 (2H,m) ,5.60 (lH,brs), 6.04 (lH,brs) .
[0256]
5 Example 42
Synthesis of
N-methyl-N-(2,2,2-trifluoroethoxycarbonyl)-L-valinonitrile
(hereinafter referred to as the compound (XIX))
[0257]
[0258]
The reaction was carried out in the same manner as in Example
2, except that the compound (XVIII) was usedinsteadofthe compound
(I), and 4.27 g of the compound (XVIII) was used. At that time,
15 purification was carried out not by distillation, but by column
chromatography.
Quantity of colorless oily substance: 3.36 g (Yield: 85%)
'H NMR(CDCl3)
60.94 (3H,d, J=6.34Hz), 1.18 (3H, d, J=6.34Hz), 2.13 (lH,m) ,3.01(3H, s)
20 ,4.4-4.6 (2H,m), 4.80 (lH,d, J=l0.73Hz).
[0259]
Example 43
Synthesis of - ~ ~~
(2s)- 3-methyl-~2-methyl-~(22-, 2,2 -trifluoroethoxycarbonyl)- buta
25 ne-1,2-diamine hydrochloride (hereinafter referred to as the
compound (XX) )
[0260]
~~c-0 I F,C-o aNxW I
CH3 CH3 e HCI
[0261]
5 The reaction was carried out in the same manner as in Example
5, except that the compound (XIX) \./asu sed instead of the compound
(IT), and 2.40 g of the compound (XIX) was used.
Quantity of white solid: 2.49 g (Yield: 89%)
' H
10 NMR(DMS0-ds) 60.77 (3H, d, J=6.34Hz), 0.93 (3H,d, J=6.34Hz), 1.83 (1H,m)
2.76( 3tl,s),3 .00 (2H,m), 3.77( 1H,m), 4.60( 1H,m),4 .77 (1H,m)J .99 (3
H,brs) .
[0262]
Example 44
15 Synthesis of
(2s)- 3-methyl-~~-methyl-4~-~ (-t{r i~luorometh~ble)n zoyl}-~~(-2 ,2
,2-trif luoroethoxycarbonyl) -butane-1, 2-diamine
[02631
The reaction was carried out in the same manner as in Example -
9, except that the compound (XX) was used instead of the compound
(III), 4-(trifluoromethy1)benzoyl chloride was used instead of
toluic acid chloride, and 0.3 g of the compound (XX) was used.
Quantity of white solid: 0.43 g (Yield: 96%)
'H NMR (CDC13)
, brs, J=minor) ,6.55 (1H, brs,major) ,7.78 (2H,m), 7.81 (2H,m) .
I02651
Example 45
Synthesis of
10 (2s) -3-methyl-~'-[ 4- (trifluoromethyl)b enzoyll-N'- (benzofuran-2
carbony1)-butane-1,2-diamine
[0266]
[0267]
15 To 5 mlof THE containing 0.28 g of benzofuran-2-carboxylic acid
was added 0.33 g of N,N' -carbonyldiimidazole and the resulting
mixture was stirred for 1 hour to prepare
N-(benzofuran-2-carbony1)-imidazole. 0.23 g of imidazole and 0.3
g of the compound (111) were sequentially added to the solution
20 and reacted for 3 hours. Ethyl acetate and water were added to
the solution , and to carried out liquid separation. Thereafter,
IN hydrochloride, a saturated aqueous solution of sodium hydrogen
-,,-,- bmu nate~anda saturated sodii.~m chl.oride solution were
sequentially separated from the organic layer. The obtained
25 organic layer was dried over sodium sulfate and filtered, and then
the solvent was distilled off under reduced pressure. To the
residue was added IPE and the vihlte precipitate was filtered. The
obtained compound was the title compound.
Quantlty of whlte solid: 0.35 g (Yield: 84%)
5 102681
Accordmg to the present invention, it is posslble to provide
a process which is advantageous to industrial production of
ethylenediamine derivatives having a halogenated carbamate group
andan acyl group, andits value for industrial application is high.
i 10
WE CLAIM:
1. A process for producing a compound represented by the
gcncral formuls (1) comprising;
producing a compound represented by the general formula (1)
by reacting a compound represented by the general formula (5)
with a deoxidizing agent,
wherein, in the formula, R1 represents an alkyl group
having 1 to 6 carbon atoms which is substituted with at least
one halogen atom or a cycloalkyl group having 3 to 6 carbon
atoms which is substituted with at least one halogen atom; R2
represents a hydrogen atom, an alkyl group having 1 to 6
carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms,
an aryl group which may be substituted or a heteroaryl group
which may be substituted; R3 and R4 each independently
represent a hydrogen atom, an alkyl group having 1 to 6 carbon
atoms which may be substituted, a cycloalkyl group having 3 to
6 carbon atoms which may be substituted, an aryl group which
may be substituted, an arylalkyl group which may be
substituted, a heteroaryl group which may be substituted or a
heteroarylalkyl group which may be substituted; and R3 and R4
may be bonded with each other to form a ring structure having
3 to 6 carbon atoms, or any one of R3 and R4 may be bonded
with R2 to form a ring structure having 5 to 6 atoms in total
(4 to 5 carbon atoms and 1 nitrogen atom),
wherein, in the formula, R1, R2, R3 and R4 are the same as
those described above,
converting the compound represented by the general formula
(1) into a compound represented by the general formula (2) by
performing the catalytic hydrogenation of the compound
represented by the general formula (1) in the presence of an
acid, and
reacting the compound represented by the general formula
(2) with a compound represented by the general formula ( 3 ) ,
wherein, in the formula, R1, R2, R3 and R4 are the same as
those described above,
wherein, in the formula, R5 represents an alkyl group
having 1 to 6 carbon atoms which may be substituted, a
cycloalkyl group having 3 to 6 carbon atoms which may be
substituted, an aryl group which may be substituted, an
arylalkyl group which may be substituted, a heteroaryl group
which may be substituted or a heteroarylalkyl group which may
be substituted; and X represents a leaving group,
wherein, in the formula, R1, R2, R3, R4 and R5 are the same
as those described above.
2. The process for producing a compound represented by the
general formula (4) as set forth in claim 1, in which the
compound represented by the general formula (5) is obtained by
reacting a compound represented by the general formula (6)
with a compound represented by the general formula (7) in the
presence of water,
wherein, in the formula, R2, R3 and R4 are the same as
those described above,
0
wherein, in the formula, R1 is the same as those described
above; and Y represents a halogen atom.
3. The process for producing a compound represented by the
general formula (4) as set forth in claim 1, in which, in the
formulas, R1 represents an alkyl group having 1 to 6 carbon
atoms which is substituted with at least one halogen atom; R2
represents a hydrogen atom or an alkyl group having 1 to 6
carbon atoms; R3 and R4 each independently represent a
hydrogen atom, an alkyl group having 1 to 6 carbon atoms which
may be substituted, an aryl group which may be substituted or
an arylalkyl group which may be substituted, and any one of R3
and R4 may be bonded with R2 to form a ring structure having 5
to 6 atoms in total (4 to 5 carbon atoms and 1 nitrogen atom);
and R5 represents an aryl group which may be substituted or a
heteroaryl group which may be substituted.
4. The process for producing a compound represented by the
general formula (4) as set forth in claim 2, in which, in the
formula, R1 represents an alkyl group having 1 to 6 carbon
atoms which is substituted with at least one halogen atom; R2
represents a hydrogen atom or an alkyl group having 1 to 6
carbon atoms; R3 and R4 each independently represent a
hydrogen atom, an alkyl group having 1 to 6 carbon atoms which
may be substituted, an aryl group which may be substituted or
an arylalkyl group which may be substituted,. and any one of R3
and R4 may be bonded with R2 to form a ring structure having 5
to 6 atoms in total (4 to 5 carbon atoms and 1 nitrogen atom);
and R5 represents an aryl group which may be substituted or a
heteroaryl group which may be substituted.
5. The process for producing a compound represented by the
general formula (4) as set forth in claim 3, in which, in the
formula, R1 is an alkyl group having 1 to 6 carbon atoms which
is substituted with at least one fluorine atom.
6. The process for producing a compound represented by the
general formula (4) as set forth in claim 4,in which, in the
formula, R1 is an alkyl group having 1 to 6 carbon atoms which
is substituted with at least one fluorine atom.
7. A process for producing a compound represented by the
general formula (2) comprising;
converting the compound represented by the general formula
(.I) into a compound represented by the general formula (2) by
performing the catalytic hydrogenation of a compound
represented by the general formula (1) in the presence of an
acid,
wherein, in the formula, R1 represents an alkyl group
having 1 to 6 carbon atoms which is substituted with at least
one halogen atom or a cycloalkyl group having 3 to 6 carbon
atoms which is substituted with at least one halogen atom; R2
represents a hydrogen atom, an alkyl group having 1 to 6
carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms,
an aryl group which may be substituted or a heteroaryl group
which may be substituted; R3 and R4 each independently
represent a hydrogen atom, an alkyl group having 1 to 6 carbon
atoms which may be substituted, a cycloalkyl group having 3 to
6 carbon atoms which may be substituted, an aryl group which
may be substituted, an arylalkyl group which may be
substituted, a heteroaryl group which may be substituted or a
heteroarylalkyl group which may be substituted; and R3 and R4
may be bonded with each other to form a ring structure having
3 to 6 carbon atoms, or any one of R3 and R4 may be bonded
with R2 to form a ring structure having 5 to 6 atoms in total
(4 to 5 carbon atoms and 1 nitrogen atom),
wherein, in the formula, R1, R2, R3 and R4 are the same as
those described above.
8. The process for producing a compound represented by the
general formula (2) as set forth in claim 7, in which, in the
formulas, R1 represents an alkyl group having 1 to 6 carbon
atoms which is substituted with at least one halogen atom; R2
represents a hydrogen atom or an alkyl group having 1 to 6
carbon atoms; and R3 and R4 each independently represent a
hydrogen atom, an alkyl group having 1 to 6 carbon atoms which
may be substituted, an aryl group which may be substituted or
an arylalkyl group which may be substituted, and any one of R3
and R4 may be bonded with R2 to form a ring structure having 5
to 6 atoms in total (4 to 5 carbon atoms and 1 nitrogen atom).
9. The process for producing a compound represented by the
general formula (2) as set forth in claim 8, in which, in the
formula, R1 is an alkyl group having 1 to 6 carbon atoms which
is substituted with at least one fluorine atom.
10. A process for producing a compound represented by the
general formula (1) comprising;
converting the resulting product into a compound
represented by the general formula (1) by reacting a compound
represented by the general formula (5) with a deoxidizing
agent,
wherein, in the formula, R1 represents an alkyl group
having 1 to 6 carbon atoms which is substituted with at least
one halogen atom or a cycloalkyl group having 3 to 6 carbon
atoms which is substituted with at least one halogen atom; R2
represents a hydrogen atom, an alkyl group having 1 to 6
carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms,
an aryl group which may be substituted or a heteroaryl group
which may be substituted; R3 and R4 each independently
represent a hydrogen atom, an alkyl group having 1 to 6 carbon
atoms which may be substituted, a cycloalkyl group having 3 to
6 carbon atoms which may be substituted, an aryl group which
may be substituted, an arylalkyl group which may be
substituted, a heteroaryl group which may be substituted or a
heteroarylalkyl group which may be substituted; and R3 and R4
may be bonded with each other to form a ring structure having
3 to 6 carbon atoms, or any one of R3 and R4 may be bonded
with R2 to form a ring structure having 5 to 6 atoms in total
(4 to 5 carbon atoms and 1 nitrogen atom),
wherein, in the formula, R1, R2, R3 and R4 are the same as
those described above.
11. The process for producing a compound represented by the
general formula (1) as set forth in claim 10, in which, in the
formulas, R1 represents an alkyl group having 1 to 6 carbon
atoms which is substituted with at least one halogen atom; R2
represents a hydrogen atom or an alkyl group having 1 to 6
carbon atoms; and R3 and R4 each independently represent a
hydrogen atom, an alkyl group having 1 to 6 carbon atoms which
may be substituted, an aryl group which may be substituted or
an arylalkyl group which may be substituted, and any one of R3
and R4 may be bonded with R2 to form a ring structure having 5
to 6 atoms in total (4 to 5 carbon atoms and 1 nitrogen atom).
12. The process for producing a compound represented by the
general formula (1) as set forth in claim 11, in which, in the
formula, R1 is an alkyl group having 1 to 6 carbon atoms which
is substituted with at least one fluorine atom.
13. A process for producing a compound represented by the
general formula (5) comprising;
converting the resulting product into a compound
represented by the general formula (5) by reacting a compound
represented by the general formula (6) with a compound
represented by the general formula (7) in the presence of
water,
wherein, in the formula, R2 represents a hydrogen atom, an
alkyl group having 1 to 6 carbon atoms, a cycloalkyl group
having 3 to 6 carbon atoms, an aryl group which may be
substituted or a heteroaryl group which may be substituted; R3
and R4 each independently represent a hydrogen atom, an alkyl
group having 1 to 6 carbon atoms which may be substituted, a
cycloalkyl group having 3 to 6 carbon atoms which may be
substituted, an aryl group which may be substituted, an
arylalkyl group which may be substituted, a heteroaryl group
which may be substituted or a heteroarylalkyl group which may
be substituyed; and R3 and R4 may be bonded with each other to
form a ring structure having 3 to 6 carbon atoms, or any one
of R3 and R4 may be bonded with R2 to form a ring,structure
having 5 to 6 atoms in total (4 to 5 carbon atoms and 1
nitrogen atom),
wherein, in the formula, R1 represents an alkyl group
having 1 to 6 carbon atoms which is substituted with at least
one halogen atom or a cycloalkyl group having 3 to 6 carbon
atoms which is substituted with at least one halogen atom; and
Y'represents a halogen atom,
wherein, in the formula, Rl, R2, R3 and R4 are the same as
those described above.
14. The process for producing a compound represented by the
general formula (5) as set forth in claim 13, in which, in the
formulas, R1 represents an alkyl group having 1 to 6 carbon
atoms which is substituted with at least one halogen atom; R2
represents a hydrogen atom or an alkyl group having 1 to 6
carbon atoms; and R3 and R4 each independently represent a
hydrogen atom, an alkyl group having 1 to 6 carbon atoms which
may be substituted, an aryl group which may be substituted or
an arylalkyl group which may be substituted, and any one of R3
and R4 may be bonded with R2 to form a ring structure having 5
to 6 atoms in total (4 to 5 carbon atoms and 1 nitrogen atom).
15. The process for producing a compound represented by the
general formula (5) as set forth in claim 14, in which, in the
formula, R1 is an alkyl group having 1 to 6 carbon atoms which
is substituted with at least one fluorine atom.
wherein, in the formula, R1 represents an alkyl group
having 1 to 6 carbon atoms which is substituted with at least
one fluorine atom or a cycloalkyl group having 3 to 6 carbon
atoms which is substituted with at least one fluorine atom; R2
represents a hydrogen atom, an alkyl group having 1 to 6
carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms,
an aryl group which may be substituted or a heteroaryl group
which may be substituted; R3 and R4 each independently
represent.a hydrogen atom, an alkyl group having 1 to 6 carbon
atoms which may be substituted, a cycloalkyl group having 3 to
6 carbon atoms which may be substituted, an aryl group which
may be substituted, an arylalkyl group which may be
substituted, a heteroaryl group which may be substituted or a
heteroarylalkyl group which may be substituted; and R3 and R4
may be bonded with each other to form a ring structure having
3 to 6 carbon atoms, or any one of R3 and R4 may be bonded
with R2 to form a ring structure having 5 to 6 atoms in total
(4 to 5 carbon atoms and 1 nitrogen atom); and Q is an
aminomethyl group, a cyano group or a carbamoyl group.
17. The compound represented by the general formula (2) as set
forth in claim 16,
wherein, in the formula, R1 represents an alkyl group
having 1 to 6 carbon atoms which is substituted with at least
one fluorine atom or a cycloalkyl group having 3 to 6 carbon
atoms which is substituted with at least one fluorine atom; R2
represents a hydrogen atom, an alkyl group having 1 to 6
carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms,
an aryl group which may be substituted or a heteroaryl group
which may be substituted; R3 and R4 each independently
represent a hydrogen atom, an alkyl group having 1 to 6 carbon
atoms which may be substituted, a cycloalkyl group having 3 to
6 carbon atoms which may be substituted, an aryl group which
may be substituted, an arylalkyl group which may be
substituted, a heteroaryl group which may be substituted or a
heteroarylalkyl group which may be substituted; and R3 and R4
may be bonded with each other to form a ring structure having
3 to 6 carbon atoms, or any one of R3 and R4 may be bonded
with R2 to form a ring structure having 5 to 6 atoms in total
(4 to 5 carbon atoms and 1 nitrogen atom).
18. The compound represented by the general formula (2) as set
forth in claim 17, wherein, in the formula, R1 represents an
alkyl group having 1 to 6 carbon atoms which is substituted
with at least one fluorine atom; R2 represents a hydrogen atom
or an alkyl group having 1 to 6 carbon atoms; and R3 and R4
each independently represent a hydrogen atom, an alkyl group
having 1 to 6 carbon atoms which may be substituted, an aryl
group which may be substituted or an arylalkyl group which may
be substituted, and any one of R3 and R4 may be bonded with R2
to form a ring structure having 5 to 6 atoms in total (4 to 5
carbon atoms and 1 nitrogen atom).
19. The compound represented by the general formula (1) as set
forth in claim 16,
wherein, in the formula, R1 represents an alkyl group
having 1 to 6 carbon atoms which is substituted with at least
one fluorine atom or a cycloalkyl group having 3 to 6 carbon
atoms which is substituted with at least one fluorine atom; R2
represents a hydrogen atom, an alkyl group having 1 to 6
carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms,
an aryl group which may be substituted or a heteroaryl group
which may be substituted; R3 and R4 each independently
represent a hydrogen atom, an alkyl group having 1 to 6 carbon
atoms which may be substituted, a cycloalkyl group having 3 to
6 carbon atoms which may be substituted, an aryl group which
may be substituted, an arylalkyl group which may be
substituted, a heteroaryl group which may be substituted or a
heteroarylalkyl group which may be substituted; and R3 and R4
may be bonded with each other to form a ring structure having
3 to 6 carbon atoms, or any one of R3 and R4 may be bonded
with R2 to form a ring structure having 5 to 6 atoms in total
(4 to 5 carbon atoms and 1 nitrogen atom).
20. The compound represented by the general formula (1) as set
forth in claim 19, wherein, in the formula, R1 represents an
alkyl group having 1 to 6 carbon atoms which is substituted
with at least one fluorine atom; R2 represents a hydrogen atom
or an alkyl group having 1 to 6 carbon atoms; and R3 and R4
each independently represent a hydrogen atom, an alkyl group
having 1 to 6 carbon atoms which may be substituted, an aryl
group which may be substituted or an arylalkyl group which may
be substituted, and any one of R3 and R4 may be bonded with R2
to form a ring structure having 5 to 6 atoms in total (4 to 5
carbon atoms and 1 nitrogen atom).
21. The compound represented by the general formula (5) as set
forth in claim 16,
wherein, in the formula, R1 represents an alkyl group
having 1 to 6 carbon atoms which is substituted with at least
one fluorine atom or a cycloalkyl group having 3 to 6 carbon
atoms which is substituted with at least one fluorine atom4 R2
represents a hydrogen atom, an alkyl group having 1 to 6
carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms,
an aryl group which may be substituted or a heteroaryl group
which may be substituted; R3 and R4 each independently
represent a hydrogen atom, an alkyl group having 1 to 6 carbon
atoms which may be substituted, a cycloalkyl group having 3 to
6 carbon atoms which may be substituted, an aryl group which
may be substituted, an arylalkyl group which may be
substituted, a heteroaryl group which may be substituted or a
heteroarylalkyl group which may be substituted; and R3 and R4
may be bonded with each other to form a ring structure having
3 to 6 carbon atoms, orany one of R3 and R4 may be bonded
with R2 to form a ring structure having 5 to 6 atoms in total
(4 to 5 carbon atoms and 1 nitrogen atom).
22. The compound represented by the general formula (5) as set
forth in claim 21, wherein, in the formula, R1 represents an
alkyl group having 1 to 6 carbon atoms which is substituted
with at least one fluorine atom; R2 represents a hydrogen atom
or an alkyl group having 1 to 6 carbon atoms; and R3 and R4
each independently represent a hydrogen atom, an alkyl group
having 1 to 6 carbon atoms which may be substituted, an aryl
group which may be substituted or an arylalkyl group which may
be substituted, and any one of R3 and R4 may be bonded with R2
to form a ring structure having 5 to 6 atoms in total (4 to 5
carbon atoms and 1 nitrogen atom).