[TITLE OFINVENTION]
PREPARATION METHOD OF INTERMEDIATE COMPOUND FOR
SYNTHESIZING MEDICAMENT
[TECHNICAL FIELD]
The present invention relates to a method for
efficiently preparlng an amidine compound which lS
essentially used for preparing a
10 dihydropyridopyrimidine intermediate compound used
for the synthesis of diabetes therapeutic agents that
inhibit dipeptidyl peptidase-TV (hereinafter referred
to as "DPP-IV").
15 [BACKGROUND ART]
20
25
It is known that compounds useful as diabetes
therapeutic agents that inhibit dipeptidyl peptidaseTV
(DPP-IV) disclosed in International Publication
W02006/104356 (see the compound of Formula 1 in
W02006/104356) exhibit
against DPP-IV enzyme
used for the treatment
excellent inhibitory activity
and thus can be effectively
and prevention of diabetes,
obesity, are diseases induced
enzymes.
inhibitor
etc. ,
For
which
the preparation of these
by the
DPP-IV
compounds, W02006/104356 discloses a
1
5
preparation method using a compound of Formula 1 as a
key intermediate (see Reaction Scheme 1 of WO
2006/104356). This method has a problem that a
substance of Formula 2 below, which is essentially
used for preparing the
expensive. In addition,
compound of Formula
methods of converting
1, is
amide
into amidine are known i~ several prior literatures,
and they can be broadly divided into two methods. One
lS a method of condensation-reacting amides with
10 amines in the presence of a dehydrating reagent
(phosphorus pentoxide, etc.), and the other is a
method of adding amines to activated amides using a
strong electrophile such as trifluoromethanesulfonic
anhydride (triflic anhydride). However, there lS a
15 disadvantage that these reactions mostly occur under
vigorous conditions which are undesirable in terms of
production.
[DETAILED DESCRIPTION OF THE INVENTION]
20 [Technical · Pxobbem]
The present invention has been devised to solve
the above-mentioned problems, and an
present invention is to provide
efficiently producing a compound of
object of the
a method for
Formula 2 below
25 under mild conditions, the compound being essentially
2
used for preparlng a compound of Formula 1 below
which is an intermediate used for the synthesis of
diabetes therapeutic agents that inhibit DPP-IV.
5 [Technical Solution]
10
15
In order to achieve the above object, the
present invention provides a novel preparation method
of a compound of Formula 2 below which is essentially
used for preparing a compound of Formula 1 below
which is a key intermediate of
disclosed ln in International
W02006/104356 as DPP-IV inhibitors.
[Formula 2]
f\JH
JL K~.-r:....y / ~-f'-'H 'J ~
wherein,
Rl is hydrogen or CF 3 ;
the compounds
Publication
R2 is selected from the group consisting of
2Q- hydrogen, substituted or unsubstituted C1 -C10 alkyl,
3
substituted
substituted
or
or
unsubstituted
unsubstituted
cycloalkyl,
aryl, and
substituted and unsubstituted C3 -C7 heteroaryl;
R3, R4 and R5 are each independently hydrogen,
5 substituted or unsubstituted Cl-C4 alkyl; and
Pl represents an amine
preferably t-butyloxycarbonyl.
protecting group,
In the above definitions,
the cycloalkyl and the
when the C 1 -C10 alkyl,
c3-c7 heteroaryl are
10 substituted, they are preferably substituted with a
halo group or a hydroxy group. When the C4 -C8 aryl is
substituted, it is preferably substituted with a halo
group, a hydroxy group or a substituted or
unsubsti tuted C1 -C4 alkyl group (which may be
15 substituted with a halo group or a hydroxy group)
The heteroaryl may include one or more
heteroatoms selected from the group consisting of N,
0 and S, and preferred examples thereof include 2-
furan, 3-furan, 2-thiophene, 2-pyridine, ]-pyridine,
20 4 -pyridine, 2~pyrrole, 3 -pyr role and the 1 ike, which
may be a form of substitution as defined above.
The method for preparing the compound of Formula
2 according to the present invention comprises
converting a compound of Formula 4 below into a
25 compound of Formula 3 below and then continuously
4
producing the compound of Formula 2 under ammonia
conditions.
Specifically, rn the preparation method
according to the pres~nt invention, a step of
5 converting a compound of Formula 4 below into a
compound of Formula 3 below (a first step) can be
carried o\it by converting the compound of Formula 4
into the compound of Formula 3 in a solvent in the
presence of pyridine and/or dichloromethane, methane
10 sulfonyl chloride (MsCl) and trifluoroacetic
anhydride (TFAA). Subsequently, the compound of
Formula 3 produced rn gaseous form can be reacted
continuously with an ammonia solution to produce a
compound of Formula 2 (Step 2) . The reaction to be
15 carried out in the preparation method of each of
these stages rs as shown in Reaction Scheme 1 below.
[Reaction Scheme 1]
R2--==N
{4) (3) (2)
wherein,
20 R2 is selected from the group consisting of
hydrogen, substituted or unsubstituted C1 -C 10 alkyl,
5
substituted or unsubstituted cycloalkyl,
substituted or unsubstituted C4 -C8 aryl, and
substituted and unsubstituted C3 -C7 heteroaryl.
Hereinafter, the preparation method of the
5 present invention according to Reaction Scheme 1 will
be described in more detail.
In the preparation of the compound of Formula 3
which is the first step of Reaction Scheme 1, the
compound of Formula 4 used may be, for example,
10 trifluoroacetamide. The compound of Formula 4, such
as trifluoroacetamide, may be reacted with a mixed
solution of one or more substances selected from the
15
group consisting of methanesulfonyl chloride (MsCl),
(TfCl),
and
trifluoromethanesulfonyl
toluenesulfonyl chloride
bromobenzenesulfonyl chloride
methanesulfonyl chloride,
chloride
(TsCl)
(BsCl), preferably
with trifluoroacetic
anhydride (TFAA), in the presence of pyridine and/or
dichloromethane, to produce the compound of Formula 3
20 in which trifluoroacetamide is substituted with
trifluoroacetonitrile (CF 3CN) to produce a nitrile as
an amide group of Formula 4.
In the preparation of the compound of Formula 2
which is the second step of Reaction Scheme 1, the
25 compound of Formula 3 produced rn the first step is
6
reacted with an ammonra solution in which an ammonia
is contained in a solvent selected from the group
consisting of isopropyl alcohol,
methyl alcohol, preferably an
ethyl alcohol and
ammonia isopropyl
5 alcohol solution in which an ammonia rs contained in
isopropyl alcohol, to produce the compound of Formula
2. In a preferred embodiment, in the second step, the
compound of Formula 3 produced in the first step may
be in gaseous form. The gaseous compound of Formula 3
10 (e.g., trifluoronitrile gas (CF3CN gas)) is bubbled
through an ammonra solution and allowed to react to
obtain the compound of Formula 2. In the case of
using the ammonia solution, especially ammonia
isopropyl alcohol, the compound of Formula 2 can be
15 continuously reacted with the compound of Formula 5
without subsequent purification step to produce a
compound of Formula 1 below. In this case, the
problem of lowering the reaction yield does not occur
and the compound of Formula 1 can be produced with
20 excellent rea·ction ·yield.
In another aspect, the present invention relates
to a method for preparing a compound of Formula 1,
the method comprising the steps of:
(a) converting the compound of Formula 4 into
25 the compound of Formula 3;
7
(b) reacting the compound of Formula 3 prepared
in the step (a) with an ammonia solution to prepare
the compound of Formula 2; and
(c) ~yclizing the compound of formula 2 prepared
5 in the step (b) with the compound of Formula (5) to
prepare a compound of formula 1.
The steps (a) and (b) are as shown in the
Reaction Scheme 1 described above, and the step (c)
is as shown in Reaction Scheme 2 below.
10 [Reaction Scheme 2]
R5
{5) (1)
wherein,
Rl is hydrogen or CF3 ;
R2 is selected from the group consisting of
15 hydrogen, substituted or unsubstituted C1 -C10 alkyl,
substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl, and
substituted and unsubstituted C3 -C7 heteroaryl;
R3, R4 and RS are each independently hydrogen,
20 substituted or unsubstituted Cl-C4 alkyl; and
Pl represents an amine protecting group,
8
preferably t-butyloxycarbonyl.
Each step will be described in detail below.
The steps (a) and (b) all are steps of preparing
the compound of Formula 2, which can be carried out
5 in the same manner as described in the method for
preparing the compound of Formula 2.
Further, the step- (c) is a step of reacting the
compound of Formula 5 with the compound of Formula 2
to obtain the compound of Formula 1, and specifically,
10 it is characterized in that the compound of Formula 2
is cyclized with the compound of Formula 5 by using
substances selected from the group consisting of a
base, an acid, a metal catalyst and an organic
catalyst, either singly or in combination, or under a
15 condition not containing all of the above substances,
to obtain the compound of Formula 1. Herein, as the
base, substances selected from the group consisting
of cl-c4 trialkylamine, diisopropylethylenediamine
(DIPEA, Hunig' s base), pyridine, K2 C03 , KOH, NaOH,
20 NaOMe, NaOEt, Cs2 C03 and LiOH may be used singly or
in combination. As the acid catalyst, substances
selected from the group consisting of TsOH and AcOH
may be used singly or rn combination. As the metal
catalyst, a substance selected from the group
25 consisting of Cu, In, Mn, Zn and Al may be used
9
singly or in combination. As the organic catalyst,
substances
NaOAc and
selected
BF30Et2
from the
may be
group consisting
used singly or
combination, and preferably, pyridine is used.
of
in
5 As the reaction solvent, isopropyl alcohol (IPA),
ethyl alcohol, methyl alcohol, n~butyl alcohol, t~
butyl alcohol, sec~butyl alcohol, toluene, ethyl
acetate or the like may be used as a single solvent
or a mixed solvent, and preferably, isopropyl alcohol
10 can be used. The reaction can be carried out at any
temperature ranging from room temperature to reflux
temperature, and preferably at 70 to 90°C.
The preparation method of the compound of
Formula 2 of the present invention is advantageous in
15 that the compound of Formula 2 can be easily produced
under mild reaction conditions, unlike the case of
using vigorous conditions, which is undesirable in
20
terms of production
amidine in the past.
when converting
Furthermore, the
Formula 2 dissD'lved in solution is
amide into
compound of
suitable for
producing the compound of Formula 1 with high yield
and purity by continuously reacting with the compound
of Formula 5 without another purification step.
Accordingly, in another aspect, the present
25 invention provides a method-for preparing a compound
10
exhibiting inhibitory activity against dipeptidyl
peptidase IV (hereinafter referred to as 'DPP-IV') of
Formula 8 below, the method comprising the steps of:
(a) converting the compound of Formula 4 into
5 the compound of Formula 3;
(b) reacting the compound of Formula 3 prepared
in the step (a) with an ammonia solution to prepare a
compound of Formula 2;
(c) cyclizing the compound of Formula 2 prepared
10 in the step (b) with the compound of Formula 5 to
prepare a compound of Formula 1;
(d) deprotecting the compound of Formula 1 and
introducing it into a compound of Formula 6 below to
prepare a compound of Formula 7 below; and
15 (e) deprotecting the compound of Formula 7 to
prepare a compound of formula 8 below.
The steps (a) to (c) are as shown in the
Reaction Schemes 1 and 2 described above, and the
20 steps (d) and '('e) are as shown in Reaction Scheme 3
below.
[Reaction Scheme 3]
11
5
10
HO~B
0 NHP2
(6)
wherein,
A lS
B is
R1
N ~
II ----::
R2~N
0
R9 R8
a) A~B b)
0 NHP2
(7)
R3
R4
R5
R6
R7
P2 represents an amine protecting
preferably Boc(t-butyloxycarbonyl),
(fluorenylmethyloxycarbonyl chloride) or
(carbamazepine),
Rl to R5 are as defined above, and
(8)
group,
Fmoc
Cbz
R6, R7, R8 and R9 are each independently
hydrogen, halogen, or substituted or unsubstituted
c1-C4 alkyl.
Specifically, in the Reaction Scheme 3, the
12
compound of Formula 8 having DPP-IV inhibitory
effects can be obtained by adding the compound of
Formula 1 and introducing it in the Formula 6 via a
coupling reaction to produce the compound of Formula
5 7, which is an amide having A as an amine group, and
then removing an amine protecting group P2.
As one specific example, the- coupling reaction
of the compound of Formula 6 and the compound of
Formula 1 can be carried out by adding EDC and HOBT.
10 In the deprotection of the amine protecting group P2,
the reaction can be carried out by removing with a
strong acid including TFA or HCl when P2 is Boc, with
HdPd/C or TMSI in the case of Cbz, and with Et 2 NH in
the case of Fmoc.
15 Further, the compound of Formula 6 may be
prepared by Reaction Scheme 4 below.
[Reaction Scheme 4]
R? 0 go go P,O~NH a) P,O~N R6 c) HO~N R6
II I 2 + - II i - II l
0 NHP G10X08 OP, b) 0 NHP, 0 NHP2
2 R9 R6 R7 R7
R9 R8 R9 R8
(9) (1 0) (11) (6)
20 wherein,
P2 is an amine protecting group, as defined
above, and
13
5
10
P3 and P4 are independently a benzyl group,
methyl group, ethyl group, i-propyl group or a tbutyl
group, and
G1 is_ good leaving group with oxygen.
triflate
tosylate,
(trifluoromethanesulfonate),
besylate or
G10 is
mesylate,
nonaflate
(nonafluorobutanesulfonate), -preferably, triflate or
nonaflate.
Specifically, the above Reaction Scheme 4 may
comprise the steps shown below:
(i) conducting coupling reaction by addition of
a base to the compound of formula 9 and the compound
15 of formula 10;
(ii) cyclizing the product of the step (i) by
addition of an acid to obtain the compound of formula
11; and
(iii) removing the carboxylic acid protecting
20 group by hydrolysis of the resulting compound of
formula 11 to obtain the compound of formula 6.
25
In the Reaction Scheme 4, a) lS a base such as
Et3N, Hunig' s base, etc.;
14
5
10
b) is an acid such as AcOH, etc., and an organic
solvent such as CH 2 Cl2 , etc.;
c) varies with
typically lS selected
the
from
protecting group and
the conditions (1) a
strong acid
and Boc2 0,
P2 is Boc
such as H2 S04,
and (2) NaOH,
and P3 is
etc. and CH 2 Cl2 , aq. NaOH,
EtOH, H20 and reflux, when
t-butyl group or is the
hydrolysis condition utilizing the base specified ln
the above condition (2), when Pl is Boc and P2 is
benzyl
group.
group, methyl
R6, R7, R8,
defined above.
group,
R9, P2,
ethyl
P3,
group and i-propyl
P4 and Gl are as
Specifically, in step (a) the unprotected
15 primary amine of the compound of formula 9 is coupled
with a carbon atom having the leaving group ln the
compound of formula 10 under the basic condition, and
-OGl is removed. This reaction uses Cl-C4
20
trialkylamine, preferably triethylamine or
diisopropylFthylamine, as the base. As the reaction
solvent, common organic solvents
dichloroethane or dichloromethane, or
(e.g., tetrahydrofuran (THF) or dioxane)
To facilitate the reaction, the
such as
cyclic ethers
can be used.
base used
25 alternatively serves as the solvent. The reaction can
15
5
be conducted at any temperature between 0° C, and the
refluxing temperature.
In step ( b I , the compound of formula 11 is
synthesized through cyclization of the
amine group of the compound produced from
( a ) , with the intern a 1 ester group under
condition. In this reaction, as the acid
secondary
said step
the acidic
inorganic
acids such as hydrochloric acid, sulfuric acid,
10 nitric acid, phosphoric acid, etc. or organlc acids
such as formic acid, acetic acid, tartaric acid, etc.
can be used, with acetic acid being particularly
preferable. The solvent and temperature conditions as
described ln the above step (a) can be used in this
15 step. Said steps (a) and (b) are conducted in a
continuous manner.
In step (c), the compound of formula 11 obtained
from step (b) is hydrolyzed to obtain the compound of
20 formula 6. S"f>ecificall'y, in case of the compound of
formula 11 where P2 is Boc and P3 is t-butyl group,
first a strong acid such as
hydrochloric acid, phosphoric
sulfuric
acid,
acid,
TFA
(trifluoroacetic acid), etc. can be used to remove
25 both protecting groups and Boc protecting group can
16
5
then be attached again to the amine group under the
basic condition to obtain the desired compound of
formula 6. Alternatively, the
basic condition, rather than
hydrolysis
the acidic
under the
condition,
can lead to selective removal
protecting
of formula
groups P2 and P3 to
6;- and this manner
of only
provide
of the
P3 among the
the compound
proced-ure lS
more efficient. Preferably, sodium hydroxide solution
is used as the base. Upon completion of the reaction,
10 the compound of formula 6 can be obtained as a solid
product through acidification using an acid.
15
In case of the compound where P2 is Boc and P3
is benzyl group,
propyl group, the
means of a base.
methyl group, ethyl
hydrolysis can be
The de-protecting
group or
conducted
reaction
iby
is
conducted uslng H2/Pd-C when P2 is Cbz,
Bu4N+F- when P2 is Fmoc.
or using
20 Pref-erably, the compound of formula 6 can be
25
obtained in a high yield when P3 is t-butyl group or
i-propyl group, more preferably t-butyl group, and P4
is methyl group or ethyl group.
The method for preparing the DPP-IV inhibitor
17
compound of Formula 8 is described in detail in
International Publication W02006/104356 and Korean
Patent No. 10-1378984 in addition to the abovementioned
method, Therefore, the method disclosed ln
5 this patent publication can be used without
limitation. The full disclosure of the above patent
publicatibn is incorporated herein by reference.
10
15
[ADVANTAGEOUS EFFECTS]
According to the present invention, a compound
of Formula 2 such
ethanamine required
compound of Formula
used for
as
for
1 '
2,2,2-trifluoro-1-imino-1-
the preparation of the
which lS an intermediate
essentially the
therapeutic
efficiently
agents that
prepared under
synthesis of
inhibit DPP-IV,
mild conditions,
diabetes
can be
whereby
ultimately a compound of Formula 1 can be produced
with high yield and purity, which lS thus very useful.
20 [DETAILED 'DESCRIPTION OF THE EMBODIMENTS]
Hereinafter, the configuration and effects of
the present invention will be described in more
detail by way of examples. These examples are
provided for illustrative purposes only, and are not
25 intended to limit the scope of the present invention
18
thereto.
Example 1: Synthesis of 2,2,2-trifluoro-1-imino-
1-ethanamine
5
2,2,2-Trifluoroacetamide (200.1 g) was added to
a mixed solution of dich1oromethane (1325. 8 g) and
pyridine (420.1 g) and stirred at 20°C. A mixed
solution of methanesulfonyl chloride (243. 4 g) and
10 trifluoroacetic anhydride (37.2 g) was slowly added
dropwise thereto. The trifluoroacetonitrile gas thus
produced was bubbled into an arnrnonla isopropyl
alcohol solution with molar concentration of 1. 7 to
1.9. When the reaction was completed, about 10 to 20%
15 of the reaction mixture solution was distilled under
20
reduced pressure to obtain 158.7 g of the title
compound in a state dissolved in an isopropyl alcohol
solution.
lH NMR (500 MHz, CDC1 3 ) o 8.51 (s, 2H)
Example 2: Synthesis of tert-Butyl
di(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-
d]pyrimidine-7~carboxylate
19
2,4-
To tert-butyl 3-oxo-4-(2,2,2-trifluoroacetyl)-1-
piperidinecarboxylate ( 8. 4 g) was added dropwise a
solution of 2,2,2-trifluoro-1-imino-1-ethanamine (4.7
5 g) in isopropyl alcohol ( 60 ml), and the mixture was
stirred at room temperature for 1 hour. When the
starting material tert-butyl 3-oxo-4-(2,2,2-
trifluoroacetyl)-1-piperidinecarboxylate disappeared,
pyridine (6. 8 g) was added dropwise thereto. After
10 the temperature was raised, the reaction mixture was
stirred for 6 hours or more under reflux conditions.
When the reaction was completed, purified water (40 g)
was added and slowly cooled to produce a solid. The
resulting mixture was allowed to age at about 5 to
15 l0°C for 1 hour or more, and filtered. The resulting
solid compound was washed with a mixture of ethyl
alcohol and purified water and dried under nitrogen
to obtain 8.6 g of the title compound in a yield of
81%.
20 lH NMR (500 MHz, CDC13 ) iS 1.50 (s, 9H), 3.12 (bt,
2H), 3.78 (t, 2H, J ~ 5.8 Hz), 4.85 (s, 2H)
20
5
10
15
[CLAIMS]
[Claim 1]
A method for preparing a compound of Formula 2
below,compound characterized of Formula by 4
comprising: converting a below into a compound of Formula 3 below and then continuously producing a compound of Formula 2 below under ammonia solution.
[Formula 2]f\JHR2)t_i\JH~
[Formula 2]
R2 =rJ
[Formula 3]
0
Jt_
R2--'" i·JH2
wherein,
R2 is selected from the group consisting of
hydrogen, substituted or unsubstituted C1 -C10 alkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl, and
20 substituted and unsubstituted C3-C 7 heteroaryl.
[Claim 2]
The method according to claim 1, characterized
21 in that R2 is CF 3 •
[Claim 3]
The method according to claim 1, characterized
in that the conversron of the compound of Formula 4 5 into the compound of Formula 3 is carried out in the presence of pyridine, dichloromethane, methane sulfonyl chloride (MsCl) and trifluoroacetic
anhydride (TFAA).
10
15
[Claim 4]
The method according to claim 1, characterized
in that trifluoroacetamide is reacted with a mixture
of one or more substances selected from the group
consisting of methane sulfonyl chloride
trifluoromethanesulfonyl chloride
toluenesulfonyl chloride (TsCl)
(BsCl),
(MsCl),
(TfCl),
and
bromobenzenesulfonyl chloride with
t r if l uoroacetic anhydride ( TFAA) , in the presence of
pyridine and dich1oromethane, to produce the compound
of Formula 3 in gaseous form.
20 [Claim 5]
The method according to claim 1, characterized
in that, when the compound of Formula 3 is converted
into the compound of Formula 2, the gaseous compound
of formula ( 3) is bubbled through an ammonia solution
25 in which ammonia rs dissolved in a solvent selected
22
from the group consisting of isopropyl alcohol, ethyl
alcohol and methyl alcohol ~and thus converted into
the compound of Formula 2.
[Claim 6]
5 A method for preparing a compound of Formula 1
below, characterized by comprising the steps of:
(a) conver-t:ing a compound of Formula 4 l5elow
into a compound of Formula 3 below;
(b) reacting the compound of Formula 3 prepared
10 in the step (a) with an ammonia solution to prepare a
compound of Formula 2 below; and
(c) cyclizing the compound of formula 2 prepared
in the step (b) with a compound of Formula (5) below
to prepare the compound of formula 1.
15
[Formula 2]
[Formula 3]
23
5
10
15
"K"L ---=-=r·.J
[Formula 4]
0 Jl K2- - [·.JH_
L
[Formula 5]
R1 -- R3 oJ£1"4
0/ ,_T/ P,
R5
wherein,
Rl is hydrogen or CF 3 ;
R2 is selected from the group consisting of
hydrogen, substituted or unsubstituted C1 -C10 alkyl,
substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl, and
substituted and unsubstituted C3 -C 7 heteroaryl;
R3, R4 and R5 are each independently hydrogen,
substituted or unsubstituted Cl-C 4 alkyl; and
Pl represents t-butyloxycarbonyl as an amine
protecting group.
[Claim 7]
The method according to claim 6, characterized
in that the compound of Formula 2 prepared in the
24
step (b) is
of Formula
continuously
5 prepared
cyclized with
in the step
separation and purification steps.
[Claim 8]
the
(c)
compound
without
5 The method according to claim 6, characterized
ln that R1 and R2 are each independently CF3 •
[Claim 9]
The method according to claim 6, characterized
in that R3, R4 and RS are each independently hydrogen.
10 [Claim 10]
The method according to claim 6, characterized
ln that the cyclization reaction of the step (c) is
carried out by adding one or more substances selected
from the group consisting of a base, an acid, a metal
15 catalyst and an organic catalyst to the compound of
Formula 5 and the compound of Formula 2.
20
[Claim 11]
The method according to claim 10, characterized
in that the base lS one or more selected from the
group consisting of trialkylamine,
diisopropylethylenediamine (Hunig' s base), pyridine,
K2 C03 , KOH, NaOH, NaOMe, NaOEt, Cs 2C03 and LiOH.
[Claim 12]
The method according to claim 10, characterized
25 in that the acid catalyst is one or more selected
25
from the group consisting of TsOH and AcOH.
[Claim 13]
The method according to claim 10, characterized
in that the metal catalyst is one or more selected
5 from the group consisting of Cu, In, Mn, Zn and Al.
[Claim 14]
The method according to claim 10, characterized
in that the organic catalyst is one or more selected
from the group consisting of NaOAc and BF30Et 2 .
10 [Claim 15]
15
20
The method according to claim 10, characterized
ln that the cyc1ization reaction of the step (c) is
carried out in the presence of pyridine.
[Claim 16]
The
in that
carried
method according to c1aim 6, characterized
the cyclization reaction of the step (c) is
out without using all of the base, the acid
catalyst and the metal catalyst.
[Claim 17]
The method according to claim 6, characterized
in that the reaction solvent used in the cyclization
reaction of the step (c) is one or more solvents
selected from the group consisting of isopropyl
alcohol, ethyl alcohol, methyl alcohol, n-butyl
25 alcohol, t-butyl alcohol, sec-butyl alcohol, toluene
26
and ethyl acetate.
[Claim 18]
The method according to claim 6, characterized
in that the cyclization reaction of the step (c) lS
5 carried out at a temperature of 70 to 90"C.
10
[Claim 19]
A method for producing a DPP-IV inhibitor
compound of Formula (8) below, the method comprising
the steps of:
(a) converting a compound of Formula 4 below
into a compound of Formula 3 below;
(b) reacting the compound of Formula 3 prepared
in the step (a) with an ammonia solution to prepare a
compound of Formula 2 below;
15 (c) cyclizing the compound of Formula 2 prepared
ln the step (b) with a compound of Formula 5 below to
prepare a compound of Formula 1 below;
(d) deprotecting the compound of Formula 1 and
introducing it into a compound of Formula 6 below to
20 prepare a compound of Formula 7 below; and
(e) deprotecting the compound of Formula 7 to
prepare a compound of formula 8 below.P2 represents Boc ( t-butyloxycarbonyl), Fmoc
(fluorenylmethyloxycarbonyl chloride) or Cbz
(carbamazepine) as an amine protecting group;
10 Rl is hydrogen or CF3 ;
R2 is selected from the group consisting of
hydrogen, substituted or unsubstituted C1 -C10 alkyl,
substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl, and