METHODE DE PRODUCTION D'UN DERIVE DE SUBSTITUTION EN 1 D'ARYL-1,4-DIHYDRO-4-OXONAPHTYRIDINE; INTERMEDIAIRES A CETTE FIN ET METHODES POUR LA PRODUCTION DES INTERMEDIAIRES

PROCESS FOR PRODUCING 1-SUBSTITUTED ARYL-1, 4-DIHYDRO-4-OXONAPHTHYRIDINE DERIVATIVE, INTERMEDIATES THEREFOR AND PORCESSES FOR PRODUCING THE INTERMEDIATES

Abrégé anglais

This invention relates to 2-(5-fluoronicotinoyl)acetic
acid derivative and a salt thereof which are useful as an intermediate
for producing a 1-substituted aryl 1-1,4-dihydro-1,4-dihydro-4-
oxonaphthyridine
derivative and a process for producing the
same.

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A 2-(5-fluoronicotinoyl)acetic acid derivative of
the general formula:
<IMG>
or a salt thereof, wherein Rla represents a carboxyl-
protecting group for a pyridone carboxylic acid; R2
represents a halogen atom, a hydroxyl group, an azido group,
an optionally substituted 01_12 alkoxy, C1-12 alkylthio,
phenylthio, naphthylthio, C1-5 alkanesulfinyl,
benzenesulfinyl, naphthalenesulfirlyl, C1-5 alkanesulfonyl,
benzenesulfonyl, naphthalenesulfonyl, C1_5 alkanesulfonyloxy,
benzenesulfonyloxy, naphthalenesulfonyloxy, di-C1-5
alkoxyphosphinyloxy or diphenoxyphosphinyloxy group, a 3-
amino-1-pyrrolidinyl group in which the amino group may be
protected by an amino-protecting group for a pyridone
carboxylic acid or a 1-piperazinyl group in which the imino
group may be protected by an imino-protecting group for a
pyridone carboxylic acid; and X represents a hydrogen atom or
-n3-

a fluorine atom, wherein the optional substituent is at least
one group selected from a halogen atom, -NO2, C1-4 alkyl and
C1-4 alkoxy.
2. A 2-(5-fluoronicotinoyl)acetic acid derivative or a
salt thereof according to Claim 1, wherein R2 represents a
halogen atom, a hydroxyl group, a 3-amino-1-pyrrolidinyl
group in which the amino group may be protected by an
amino-protecting group for a pyridone carboxylic acid, a
1-piperazinyl group in which the imino group may be protected
by an imino-protecting group for a pyridone carboxylic acid
or an optionally substituted C1-12 alkoxy, C1-12 alkylthio,
phenylthio, naphthylthio, C1-5 alkanesulfonyloxy,
benzenesulfonyloxy or naphthalenesulfonyloxy group, wherein
the optional substituent is as defined in Claim 1.
3. A 2-(5-fluoronicotinoyl)acetic acid derivative or a
salt thereof according to Claim 2, wherein X represents a
fluorine atom.
4. A 2-(5-fluoronicotinoyl)acetic acid derivative or a
salt thereof according to Claim 3, wherein R2 represents a
halogen atom, a hydroxyl group, a 3-amino-1-pyrrolidinyl
group in which the amino group may be protected by an
amino-protecting group for a pyridone carboxylic acid or an
optionally substituted C1-12 alkoxy, benzenesulfonyloxy or
naphthalenesulfonyloxy group, wherein the optional
substituent is as defined in Claim 1.
-164-

5. A process for producing a 2-(5-fluoro-nicotinoyl)acetic
acid derivative of the general formula:
<IMG>
or a salt thereof, wherein R1a, R2 and X are as defined in
Claim 1, comprising: reacting a reactive derivative in the
carboxyl group of a compound of the general formula:
<IMG>
wherein R2 and X are as defined above, with a compound of the
general formula:
<IMG>
or a salt thereof, wherein R1a is as defined above and R1
represents a hydrogen atom or a carboxyl-protecting group for
a pyridone carboxylic acid, and subsequently subjecting the
-165-

product to removal of the carboxyl-protecting group of R1, if
present, and decarboxylation.
6. A process according to Claim 5, wherein R2
represents a halogen atom, a hydroxyl group, an optionally
substituted C1-12 alkoxy, benzenesulfonyloxy or
naphthalenesulfonyloxy group, a 3-amino-1-pyrrolidinyl group
in which the amino group may be protected by an
amino-protecting group for a pyridone carboxylic acid or a
1-piperazinyl group in which the imino group may be protected
by an imino-protecting group for a pyridone carboxylic acid,
wherein the optional substituent is at least one group
selected from a halogen atom, -NO2, C1-4 alkyl and C1-4
alkoxy.
7. A process according to Claim 5 or 6, wherein X is a
fluorine atom.
8. A process according to Claim 5 or 6, wherein the
reaction is effected at a temperature of -50 to 100°C.
-166-

Description

1 ~44ti43
Thls Invention relates to a novel 2-(5-fluoronicoti-
noy)acetic acid derivative of the formula CI):
0
COOf~a
R N NH
X
15
25
35

l3~Ob~~~
wherein R1a represents a carboxyl-protecting group; R2 represents
a halogen atom, a hydroxyl group, an azido group, an optionally
substituted aikoxy, alkylthio, aryithio) alkanesulfinyl)
arenesuiflnyl, alkanesulfonyt) arenesulfonyi, alkanesuifonyloxy,
arenesulfonyloxy) dialkoxyphosphinyloxy or diaryloxyphosphinylbxy
group, a 3-amino-1-pyrrolldinyl group in which the amino group
may be protect4ed or a 1-piperazinyl group in whch the Imino group
may be protected;
15
25
35
- 3 -

~3~0~~~~
and X represents a hydrogen atom or a fluorine atom, or a salt
thereof.
This application Is a divisional application of copend-
ing application No. 500,107 filed January 22, 1986.
Thus) the present invention provides a 2-(5-fluoronl-
cotlnoyi)acetic acid derivative or a salt thereof, which are use-
ful as an intermediate of a 1-substituted aryl-1,4-
15
25
35
- 4 -

~~~Ob~3
dihydro-4-oxonaphthyrldine derivative of the formula (~Tj or a
salt thereof:
O
F COOR1
E
~N'~ N
R2a X
F
wherein R1 represents a hydrogen atom or a carboxyl-protecting
group; R2a represents a 3-amino-1-pyrrolidinyi group in which the
amino group may be protected, or a 1-piperazinyl group in which
the imino group may be protected; and X represents a hydrogen
atom or fluorine atom.
The present invention also provides a process for pro-
ducing the 2-(5-fluoronicotinoyi)acetlc acid derivative of the
formula (1) industrially and easily.
In Program and Abstracts of the 24th I.C.A.A.C., pages
102 to 104 and Japanese Patent Appllcatlon Kokai (Laid-Open)
35
- 5 -

1340~~4~
No. 228,479/85) It Is disclosed that 1-substituted aryl-1,4-dlhy-
dro-4-oxanaphthyrldine derivatives of the formula (LL) and salts
thereof have a strong anti-bacterial activity against Gram-posi-
tive bacteria and Gram-negative bacteria and when they are orally
or parenterally administered a high blood level is obtained) and
they have excellent properties such as high safety and the like.
This invention also relates to the following process
for producing compounds of the formula (I) or salts thereof.
15
25
35
- 6 -

8
O 4-1
° x o
x
U
O = U z
-- m
z
0
Gc.~ N
f~
G
O
N ~
U
~ a)
Q) ~1-~
;>C
~rI 41
.~ o x
0
.~ a~ o ~ .__ ~ ._ ,
s~ o
-,
am, O z
.~ x
+~ o --
U 1~
~-I r-i C~ ~ N
Q) ~
C~ U '-'
_ 7 _

1~4~b~~
In the above formulas (I) and (~), Rya, R2 and X have the same
meanings ,as defined above.
The above-mentioned production process and intermediate
are used in the following production routes and enable the com-
pounds of the formula (ZZ) or salts thereof to be produced advan-
tageously in industry.
15
25
35
_ g _

1340b~~8
I
_ ___ __ _____~__ _ _ __ _____
0
U
f
I
I
I
y
O
rl N ~ N
1-a O
O v
o x ,~ ° x ,~;
o z O w ~ ~ o z~w
O ~ ~n O z
c~ ~ o w o 0
a~
0
a
'--~
x
U O O
o x o x
o _
w o z-~-w "~ o z O
H H
Oz v Oz ...,
fs., O
a,
__
~x x o o x o
° ~ o x
z -~-- w . ~ ~ o z O w
O H
w ~' ~ w
0
lT o
- 9 -

~.340~~~
0
v x~ ~ _
~ o
-__-_.~ o z--~O --w H ~ ~ o
-- ~ ~ a
Oz
o .u
w
N
~N
O
O
O
O N O
O
U x ~ v x
o z O w -~ o z -~-w
Oz ~ ~ Oz r. b
Iz.r M O C=-) U7 O
O
~4~
O i
1-~
Q;
PG O
O
0 0- x o x
U O z O f~~ ~ 7 O z~w
H
Oz v Oz
CZ,
W M w
O o
J
o x ~ c~ x
O O
U x~ ° °o x
Sa U z ~ t~.a
r-i N
O z .~ O z
M r- i Cj-i Ul n-1
O c~f O (d
U7
O
O U
- l~ -

0
U
A
4-a ri ' 4--!
-1 O ~ O
c~ a~ O a~
O S-I O ~-I
o a~ v x
v x ~--~
o z~w
o z Q w ~ +'
r-,
Uz
Q z ~n
b
S-1 N ~-1
- w o o c:a o 0
T
v
0
x x rx
0 0
0 o x o x
U O z ~ f-~ ~ O z ~ L=.~ ~
d'
r~ \ H
o Qz ~. Q 7 .r
W
G-.~ O L~ N
cn O
-1 4-I (li x
o x ~ ° o z~w
v z~w ~ v H a~
H ,i-.
H -1-J
Qz
r-I w N .-i
C=~ O ~d O
U1 U1 f~
O ~ O ~1
r~ S-1 ~ ~-1
.fv tY, O ~ P; O
- 1~. -

~3~Q~~~~
~:
U
O
O O
x ~, ~ x ,+~
O
O z ~ w .,~ y~ O z 0 - w
H ~ ~ N
Oz J ~ Oz
O -,-~ v-'
- C~, O - ~ ~ G~ M r-s
N ~ z
0 0
r-O-1 O O
_ ,
O .'
+-~
!x O
O
0 o x o -J x
o x ~ x
v z Q w o z Q w
r-I H
H
~z ~ ~ z
C:., O w M
O = Q, z
N
O
O
r-1
c~ x w x x u-,
o x ° ° x i
o z -~- w ,~ ~ v z
H ~
H ~'
.y
C~ O ~ C..~ M ~--a
o=w ~ z
N U7
' rd
O O _ O
- 1.2

~3~0~~~3
0
U
f
W
O
O
N
N
x
z O w ~
H r-I
x
O
O
U
U
O 4-i
f~ 1 O
J O O
o x ~ o x
x ~, x ~, as
oz~wH+~ozOwH~+~
,~ ,~ x
b
o O~ ~ Oz
w
w ~s ~ w x ro o
,.,
o w
w
x ~ o x o
0
o z ~ ~. ~. ~ o z
w ~-' ~ ~ w
Oz H
Oz
H
w ~ ~ w
N x,
O O
- 13 -
X~ J

13~~~~8
0
U
H 4-I
H O
O
O r-I
-N O C~ N
O O
!~ U --.
.1-i
II H
O U ~ rd
U y'~.a
x N Q
O
S-~
U 4-a
N Q
x a~
U x
U = z a~
x
z
x
O
w o
- 14 -

134Q~~3
In the above-mentioned production routes, R90-repre-
sents the same alkoxy group as mentioned below in R2; R1~S03-
represents the same alkanesulfonyloxy or arenesulfonyloxy group
as mentioned below In R2; R1~S- represents the same alkylthio or
arylthio group as mentioned below In R2; R1~S0-represents the
same alkanesulfinyl or arenesulfinyl group as mentioned below in
R2; R10S02- represents the same alkanesulfonyl or arenesulfonyl
gorup as mentioned below in R2;
O
(R1~0)2P0- represents the same dialkoxyphosphinyloxy or diaryl-
oxyphosphlnyloxy,group as mentioned below in R2; each of these
groups for R9 and R1~ may be substituted by at least one of the
substituents mentioned below as to the substituent for R2;
20
30
- 15 -

.~3~Qb~8
Y represents a halogen atom; Z represents a removable group which
may be a halogen atom, a hydroxyl group or an optionally substi-
tuted acyloxy, alkanesulfonyloxy, arenesulfonyloxy, dlalkoxyphos-
phinyloxy or diaryloxyphosphinyloxy group; and R1, Rla, R2a and X
have the same meansings as defined above.
This invention is explained in detail below.
15
25
35
- 16 -

' ~3~~~a4~
1 In this specification, the carboxyl-protecting
group for R1 and Rla includes those which are conventionally
used in this field, for example, the conventional carboxyl-
protecting groups mentioned in Japanese Patent Application
Kokai (Laid-Open) No. 80,665/84 such as alkyl, benzyl,
pivaloyloxymethyl, trimethylsilyl and the like.
The halogen atoms for R2, Y and Z include, for
example, fluorine, chlorine, bromine and iodine. In. R2,. tln.e
alkoxy group includes, for example, Cl_l2alkoxy groups
such as methoxy, ethoxy, n-propoxy, isobutoxy, pentyloxy,
hexyloxy, heptyloxy, octyloxy, dodecyloxy and the like;
the alkylthio group includes, for example, C1-l2alkylthio
groups such as methylthio, ethylthio, n-propylthio,
isopropylthio, isobutylthio, tert.-bu tylthio, pentylthiof
hexylthio, heptylthio, octylthio, dodecylthio and the 1._i_ke;
the arylthio group includes, for_ example, phenylthio,
naphthylthio and the like; the alkanesulfinyl group includes,
for example, C1-5alkanesulfinyl groups such as methane-
sulfinyl, ethanesulfinyl and the like; the arenesulfinyl
group includes, for example, benzenesulfinyl, naphthalene-
sulfinyl and the like; the alkanesulfonyl group includesF
for example, C1-5alkanesulfonyl groups such as methane-
sulfonyl, ethanesulfonyl and the like; the arenesulfonyl
group includes, for example, benzenesulfonyl, naphthalene-
sulfonyl and the like; the alkanesulfonyloxy group includes,
for example, Cl-5alkanesulfonyloxy groups such as methane-
sulfonyloxy, ethanesulfonyloxy and the like; the arene-
sulfonyloxy group includes, for example, benzenesulfonyloxy,
- 17 -

1 naphthalenesulfonyloxy and the like; the dialkoxyphos-
phinyloxy group includes, for example, di-C1-5alkoxy
phosphinyloxy groups such as dimethoxyphosphinyloxy,
diethoxyphosphinyloxy, dipropoxyphosphinyloxy, dibutoxy-
phosphinyloxy and the like; the diaryloxyphosphinyloay
group includes, for example, diphenoxyphosphinyloxy and the
like.
The above-mentioned alkoxy, alkylthio, aryli:.h:io,
alkanesulfinyl, arenesulfinyl, alkanesulfonyl, arene-
sulfonyl, alkanesulfonyloxy, arenesulfonyloxy, dialkoxy-
phosphinyloxy and diaryloxyphosphinyloxy groups for R2 may
be substituted by at least one substituent selected from
the group consisting of halogen atoms such as fluorine,
chlorine, bromine, iodine and the like; vitro group; lower
alkyl groups such as methyl, ethyl, n-propyl, isopropylP
n-butyl, isobutyl, sec.-butyl, tert,-butyl and the like;
lower alkoxy groups such as methoxy, ethoxy, n-propo}:y,
isopropoxy, n-butoxy, isobutoxy, sec.-butoxy, tert.-butoxy
and the like; etc.
25
- 18 -

:~3~0~~3
1
The protecting groups for the amino and imino
groups in the 3-amino-1-pyrrolidinyl group in which the
amino group may be protected and the 1-piperazinyl group
in which the imino group may be protected for R2 and R2a
include those which are conventionally used in this field,
for example, the conventional amino-protecting and imino-
protecting groups mentioned in Japanese Patent Application
Kokai (Laid-Open) No. 80,665/84 such as formyl, acetyl,
ethoxycarbonyl, benzyloxycarbonyl, N,N-dimethylaminomethylene
and the like.
The optionally substituted alkanesulfonyloxy,
arenesulfonyloxy, dialkoxyphosphinyloxy and diaryloxy-
phosphinyloxy groups for Z include those mentioned as to
R2, and the optionally substituted acyloxy group for Z
includes, for example, acetyloxy, benzoyloxy and the like.
25
- 19 -

~t3~0~~~~
In each of the above-mentioned compounds, the salt
Includes salts at the basic groups such as amino group and the
iike'and,at the acidic groups such as carboxyl group) hydroxyl
group and the Ilke. The salt at the basic group includes) for
example, salts with mineral acids such as hydrochloric acid,
hydrobromic acid, sulfuric acid and the like; salts with organic
carboxylic acids such as oxalic acid, citric acid, trifluoro-
acetic acid, and the like; salts with sulfonic acids such as
methanesulfonic acid) p-toluenesulfonlc acid, naphthalenesuifonic
acid and the like; etc. The salt at the acidic group includes,
for example, salts with alkali metals such as sodium, potassium
and the like; salts with alkaline earth metals such as magnesium,
calcium and the like; ammonium salts; and salts with nitrogen-
20
30
- 20 -

~3~p~;~~
containing organic bases such as procain, dibenzylamine, N-ben-
zyl- ~ -pi7enethylamine, 1-ephenamine, N,N-dibenzylethylenediamine,
triethylamine) pyridine; N,N-dimethylaniline) N-methylpiperidlne,
N-methyimorphollne) diethylamine, dicyclohexylamine and the like.
The process of this invention and process for producing
the present compounds are described in detail below.
15
25
35
- 21 -

(1) The compounds of the formulas (Ia), (fib), (Ic), (Id),
(Ie), (If), (Ig), (Ih), (I'J), and (,Tj) or salts thereof [namely,
the compounds of the formula (Z) or salts thereof] can be
obtained from the reactive derlvatlve In the carboxyl group of
the compounds of the formula (.T1C) which includes the compounds
of the formulas (tea) -- (~IJ) in which R1 is a hydrogen atom in
the following manners:
15
25
35
- 22 -

j34~~~8
Reactive derivative in the
carboxyl group of
F COOH
R2 N NH X
0
F
( III )
COORla
H2C~COORlb ' /COORla
(vII~-1) H2C~COOH
or asalt thereof ( vII-2)
O orasalt thereof
and de-carlaoxy--
F CCH lation
0
R2 N NH ,
0
F
(VIII;
ora salt the
Removal of carboxyl-
protecting group and
de-carboxylation
0
F CCH2COORla
0
2'~
R NH X
0
F
( I )
orasalt thereof
- 23 -

i3~0~~~3
1 In the above formulas, Rla, R2 and X have the same meanings
as defined above and Rlb represents a carboxyl-protecting
group including the same examples as those of Rla and may
be the same as or different from Rla.
The reactive derivative in the carboxyl group of
the compound of the formula (III ) includes, for example,
acid halides such as acid chloride, acid bromide and the
like; acid anhydrides, mixed acid anhydrides with monoethyl
carbonate or the like; active esters such as dinitrophenyl
ester, cyanomethyl ester, succinimidoester and the like;
active acid amides with imidazole or the like; etc.
The salts of the compounds of the formulas (rII-1 )
and (vII-2) include, for example, salts with alkali metals
such as lithium, potassium, sodium and the like; salts
with alkaline earth meta7_s such as magnesium and th.e :L:ikc.;
salts with magnesium ethoxide; etc.
Also, the salts of the compound of the formula
wmr)include the same salts as mentioned as salts of the
compound of the formula (I) and the like.
The compound of the formula ( T .) or (VIII) or a salt
thereof can be produced by reacting a reactive derivative
in the carboxyl group of the compound of the formula frll )
with a compound of the formula (vII-?~ or a salt thereof or
a compound of the formula (vII-~. ) or a salt thereof , respE'C-~
tively, in an appropriate solvent. The solvent used may
be any solvent inert to the reaction, and includes, for
example, alcohols such as methanol, ethanol, isopropyl
alcohol and the like; aromatic hydrocarbons such as benzene,
- 24

~,;~Qb4'3
1 toluene and the like; halogenated hydrocarbons such as
methylene chloride, chloroform, dichloroethane and the like;
ethers such as diethyl ether, tetrahydrofuran, dioxane and
the like; nitriles such as acetonitrile and the like;
amides such as N,N-dimethylformamide, N,N-dimethylacetamide
and the like; etc. Also, the amount of the compound of the
formula (vII-1~ or (VII-2 ) or a salt thereof used is at least
equimolar to, preferably 1.0 to 2.5 moles per mole of, th.e
reactive derivative in the carboxyl group of the compound
of the formula (III). The reaction may be effected usually
at -50 to 100°C, preferably at -20 to 70°C, for 5 minutes
to 30 hours.
In order to convert the compound of the formula
(vIII)or a salt thereof into a compound of the formula (I }
or a salt thereof, the compound of the formula (VI~I)or a
salt thereof may be subjected to removal of the carboxyl--
protecting. group of R1 arid de-carboxylation using tri-
fluoroacetic acid in anisole or p-toluenesulfonic acid i.n
a hydrous solvent.
25
- 25 -

m~o~~4
(2) The compound of the formula ( 71 Via) or a salt thereof
can be produced by reacting a compound of the formula (Q) or a
salt thereof prepared according to the method described In
British Patent No. 1,409,987 with a compound of the formula
or a salt thereof prepared based on the method described In Bull.
Soc. Chlm. Fr., pp.1,165-1,169 (1975)) J. Chem. Soc. (C).
pp. 2206-2207 (1967) and Program and Abstracts of the 105th Meet-
ing of Japanese Pharmaceutical Society p. 523 (1985).
1p The solvent which may be used In this reaction may be
any solvent Inerir to the reaction, and includes, for
20
30
- 26 -

1~~0~~-
1 example, water; alcohols such as methanol, ethanol, isopropyl
alcohol, butyl alcohol, ethylene glycol, methyl Cellosolve
and the like; aromatic hydrocarbons such as benzene, toluene
and the like; halogenated hydrocarbons such as methylene
chloride, chloroform, dichloroethane and the like; ethers
such as tetrahydrofuran, dioxane, anisole, diethylene
glycol dimethyl ether, dimethyl Cellosolve and the like;
nitriles such as acetonitrile and the like; ketones such
as acetone, methyl ethyl ketone and the like; esters such
as methyl acetate, ethyl acetate and the like; amides such
as N,N-dimethylformamide, N,N-dimethylacetamide and the
like; sulfoxides such as dimethylsulfoxide and the like;
etc. These solvents may be used in admixture of two or
more.
The condensing agent includes, for example, sor:~ium
hydroxide, potassium hydroxide, potassium tert.-butoxide,
sodium hydride, sodium methoxide, sodium ethoxide,
potassium methoxide, potassium ethoxide, and the like.
In this reaction, the amount of the compound of
the formula (vI ) or a salt thereof used is not critical
though it is at least equimolar to, preferably 1.0 to 3~0
moles per mole of, the compound of the formula ( v ) ~ 1~:~_so,
this reaction may be effected usually at 0 to 150°C,
preferably 15 to 100°C, for 5 minutes to 30 hours.
(3) Alkylation
The compound of the formula (c1-tc) or a salt there-
of, the compound of the furmula (nc) and the compound of
the formula (TVc) or a salt thereof can be produced by
27 -

~.3~0~~~8
1 reacting a compound of the formula (~I7a) or a salt thereof,
a ,compound of the formula ( za ) or a salt thereof or a
compound of the formula (zva) or a salt thereof, respec-
tively, with an alkylating agent in the presence or absence
of an acid-binding agent.
The solvent which may be used in the reaction may
be any solvent inert to the reaction, and includes, for
example, water; alcohols such as methanol, ethanol,
isopropyl alcohol, and the like; ethers such as diethyl
ether, tetrahydrofuran, dioxane and the like; ketones such
as acetone, methyl ethyl ketone and the like; esters such
as methyl acetate, ethyl acetate and the like; aromatic
hydrocarbons such as benzene, toluene and the like;
halogenated hydrocarbons such as methylene chloride,
ch7_oroform and the like; amides such as N,N-dimethylform-
amide, N,N-dimethylacetamide and the like; sulfoxides
such as dimethylsulfoxide and the like; etc. These solvents
may be used in admixture of two or more. The alkylatin.g
agent includes, for example, diazoalkanes such as diazo-
methane, diazoethane and the like; dialkyl sulfates such
as dimethyl sulfate, diethyl sulfate and the like; alkyl
halides such as methyl iodide, methyl bromide, ethyl bromide
and the like; etc.
When a dialkyl sulfate or an alkyl halide is r~.~,ed
as the alkylating agent, the acid-binding agent may be
used. The said acid-binding agent includes, for example,
inorganic bases such as an alkali hydroxide, an alkali
carbonate and the like; and amines such as trimethylamine,
- 28 _

2~~0~~~
1 triethylamine, tributylamine, N-methylpiperidine, N-methyl-
mo~pholine, lutidine, colidine, pyridine and the like. The
amount of the dialkyl sulfate or the alkyl halide which are
the alkylating agents and the amount of the optionally used
acid-binding agent are at least equimolar to, preferably
1.0 to 2.0 moles per mole of, the compound of the formula
or a salt thereof , the compound of the formula ( za -)
or a salt thereof or the compound of the formula (wa) or
a salt thereof. In this case, the reaction may be effected
usually at 0 to 150°C, preferably 0 to 50°C, for 5 minutes
to 30 hours.
When a diazoalkane is used as the alkylating
agent, the amount thereof is at least equimolar to,
preferably 1.0 to 1.5 moles per mole of, the compound of t.h.e
formula (rzza) or a salt thereof , the compound of the formula
(1a ) or a salt thereof, or the compound of the formula
~ or a salt thereof. In this case, the reaction may be
effected usually at 0 to 50°C, preferably 0 to 25°C, for .5
minutes to 30 hours.
(4) Halogenation
( i) The compounds of the formulas (wt>) and ~alW ) u.r_
salts thereof can be obtained by reacting'compounds of t~lre
formulas (wc) and (~ma) or a salts thereof , respectively,
with a halogenating agent. The solvent which may be useci.:ixi
the reaction may be any solvent inert to the reaction, and
includes, for example, aromatic hydrocarbons such as benzene,
toluene, xylene and the like; halogenated hydrocarbons such
as methylene chloride, chloroform, dichloroethane and the
_ 29 _

134~~~~
like; amides such as N,N-dimethylformamlde) N,N-dimethylacetamlde
and the like; etc. These solvents may be used In admixture of
two or more. The halogenating agent includes, for example, phos-
phorus oxychloride, phosphorus oxybromide) phosphorus pentachlo-
ride) phosphorus pentabromide) phosphorus trichloride, thionyl
chloride, phosgene and the like) and these agents may be used in
admixture of two or more and may be used as a solvent. The
amount of the halogenating agent used Is at least equimolar to
the compound of the formula (tea) or a salt thereof or the com-
pound of the formula (IYc) or a salt thereof. The reaction may
be effected usuai.ly at O to 150oC, preferably 50 to 110oC, for 30
minutes to 30 hours.
(li) The compound of the formula (Iffb) or a salt thereof can
be obtained by reacting a compound of the formula (=a) or a salt
thereof or a compound of the formula (=c), (Id), (Ih) or (11)
[hereinafter, referred to as the compound of the formula (T'-1) or
a salt thereof] with a Vllsmeler reagent derived from an N,N-di-
substituted formamide. The solvent which may be used in the
reaction may be any solvent Inert to the reaction, and Includes,
for example, aromatic hydrocarbons such as benzene, toluene,
dichlorobenzene and the like; halogenated hydrocarbons such as
methylene chloride) chloroform, dichloroethane and the like; for-
mamides such as N,N-dlmethylformamide and the like; etc. These
solvents may be used in admixture of two or more.
30
- 30 -

13~0~~~~3
The Vllsmeier reagent derived from N,N-di-substituted
formamidP includes those conventionally known as a Vilsmeler
reagent der(ved from N,r'!-di-substituted formamides, and specifi-
cally includes, for example, Vllsmeler reagents obtained by
reacting N,N-di-substituted formamides of the formula:
R7 O
NCH ~ Zy )
~8
wherein R~ and Ra, which may be the same or different, represent
alkyl or aryl groups, or may form a nitrogen-containing saturated
heterocycilc group together with the adJacent nitrogen atom, and
said ring may contain a sulfur or oxygen atom in addition to the
nitrogen atom, with an inorganic or organic halides which are
conventionally known in the Vilsmeler reaction.
25
35
- 31 -

I340b4g
1 The N,N-di-substituted formamides of the formula
( zx ) include, for example, N,N-di-C1-5alkylformamides
such as N,N-dimethylformamide, N,N-diethylformamide, N,N-
dibutylformamide and the like; N-C1-5alkyl-N-arylformamides
such as N-methylformanilide and the like; N,N-diaryl-
formamides such as N,N-diphenylformamide and the like;
N-formyl-nitrogen containing saturated heterocyclic groups
which may contain an oxygen or sulfur atom in addition to
the nitrogen atom such as N-formylpyrrolidine, N-formyl-
piperidine, N-formylmorpholine, N-formylthiomorpholine and
the like; etc.
The inorganic and organic halides include those
which are conventionally known in the preparation of
Vilsmeier reagents, and the inorganic halide includes, for
example, phosphorus halides such as phosphorus oxychloride,
phosphorus oxybromide, phosphorus t:richloride, phosphorus
tribromide, phosphorus pentachloride and the like; sulfur
halides such as thionyl chloride, thionyl bromide, sulfuryl
chloride and the like; etc. The organic halide includes,
for example, carbonyl halides such as phosgene, diphosgene,
ethyl chlorocarbonate and the like; oxalyl halides such as
oxalyl chloride and the like; organic phosphorus halides
such as dibromotriphenylphosphorane and the like; etc.
32

~~~oo~s
When the Vilsmeler reagent Is in solution, It may be
used as the solvent. In the reaction, the amount of the
Vllsmeler reagent used is at least equlmolar to,
10
20
30
- 33 -

134~b1~3
1 preferably 2.0 to 5.0 moles per mole of, the compound of
the formula ( z-1 ). The reaction may be effected usually
at 0 to 150°C, preferably 0 to 90°C, for 5 minutes to 30
hours.
The Vilsmeier reagent derived from N,N-di-
substituted formamides can be obtained by reacting an N,N-
di-substituted formamide with the inorganic or organic halide
described above, in equimolar amounts, and the preparation
of this Vilsmeier reagent may be conducted usually at 0 to
25°C for 5 minutes to 1 hour. Also, the Vilsmeier reagent
may be prepared in situ.
The reaction conditions are not limited to those
mentioned above, and may be varied depending upon the
reactants used.
(5) Sulfonylation
The compound of the formula (rrt~ or a salt thereof ,
the compound of the formula ( zd ) and the compound of the
formula (zvd) or a salt thereof can be obtained by reactizng
a compound of the formula (zzla) or a salt thereof , a compound .
of the formula (ja ) or a salt thereof and a compound of
the formula (I~a) or a salt thereof, respectively, with a
sulfonylating agent in the presence or absence of an ac:id-
binding agent. The solvent which may be used in the reaction
may be any solvent inert to the reaction, and includes,
for example, water; aromatic hydrocarbons such as benzene
toluene, xylene and the like; ethers such as dioxane,
tetrahydrofuran, anisole, diethylene glycol dimethyl ether
and the like; halogenated hydrocarbons such as methylene
- 34 -

l~~~b~
1 chloride, chloroform, dichloroethane and the like; ketones,
such as acetone, methyl ethyl ketone and the like; nitriles
such as acetonitrile and the like; amides such as N,N-
dimethylformamide, N,N-dimethylacetamide and the like;
sulfoxides such as dimethylsulfoxide and the like; hexa-
methylphosphoramide; pyridine; etc. These solvents may be
used in admixture of two or more. The sulfonylating agent
includes, for example, alkanesulfonyl and arenesulfonyl
halides such as methanesulfonyl chloride, trifluoromethane-
sulfonyl chloride, ethanesulfonyl chloride, 1-methylethane-
sulfonyl chlor.de, l,l-dimethylethanesulfonyl chloride,
benzenesulfonyl chloride, toleuensulfonyl chloride,
nitrobenzenesulfonyl chloride, chlorobenzenesulfonyl
chloride, 2,5-dichlorobenzenesulfonyl chloride, 2,3,4-tr:~m
chlorobenzenesulfonyl chloride, 2,4,5-trichlorobenzene-
sulfonyl chloride, 2,4,6-trimethylbenzenesulfonyl chloride,
2,4,6-triisopropylbenzenesulfonyl chloride, naphthanene-
sulfonyl chloride and the like; alkanesulfonic and
arenesulfonic anhydrides such as methanesulfonic anhydride,
toleuenesulfonic anhydride and the like; etc. Also, the
acid-binding agent includes, for example, inorganic and
organic bases such as triethylamine, di-isopropylethylamirxej
1,8-diazabicyclo[5,4,0]undec-7-ene(DBU), pyridine,
potassium tert.-butoxide, sodium hydride, alkali hydroxides,
alkali carbonates and the like.
The amount of the sulfonylating agent used and
the amount of the optionally used acid-binding agent are at
least equimolar to, preferably 1.0 to 2.0 moles per mole of,
- 35 -

:~~~Oe4~
1 the compound of the formula (~IIa) or a salt thereof ( the
compound of the formula (za ) or a salt thereof, or the
compound of the formula (rva) or a salt thereof. The
reaction may be effected usually at -10 to 150°C, preferably
0 to 80°C, for 5 minutes to 30 hours.
( E> ) Thiolation
In order to produce the compound of the formula
( ze ) from the , compound of the formula ( Ib ) or a salt
thereof or the compound of the formula (rc1 ) and to produce
the compound of the formula (Tie) or a salt thereof from the
compound of the formula ~III1~ or (~IId) or a salt thereof , the
compound of the formula ( Ib ) , ~ jd .) , (~IIr~ or f~iid) or a
salt thereof can be reacted with a thiol or a salt thereof
such as methanethiol, ethanethiol, n-propanethiol, 1-
methylethanethiol, isobutanethiol, l,l-dimethylethanethiolf
pentanethiol, hexanethiol, heptane:thiol, octanethiol,
dodecanethiol, thiophenol, naphthalenethiol or the like in
the presence or absence of an acid-binding agent. The
salt of the thiol includes, for example, salts at the
acidic groups as described in the case of the compound of
the formula (I) or the like. The solvent which may be used
in the reaction may be any solvent inert to the react:i_onr.
and includes, for example, aromatic hydrocarbons such as
benzene, toluene, xylene and the like; ethers such as
dioxane, tetrahydrofuran, anisole, diethylene glycol diethy7_
ether and the like; halogenated hydrocarbons such as
methylene chloride, chloroform, dichloroethane and the
like; amides such as N,N-dimethylformamide, N,N-dimethyl-
- 36 -

i340b4~
1 acetamide and the like; sulfoxides such as dimethylsulfoxide
and the like; etc. These solvents may be used in admixture
of two or more. The acid-binding agent includes, for
example, inorganic bases such as alkali hydroxides, sodium
hydride, alkali carbonates and the like; and organic bases
such as trimethylamine, triethylamine, di-isopropylethyl-
amine, DBU, potassium tert.-butoxide, tributylamine,
pyridine, N-methylpiperidine, N-methylmorpholine, lutidine,
collidine and the like. The amount of the thiol or a salt
thereof used and the amount of the optionally used acid-
binding agent are at least equimolar to, preferably 1.0
to 2.0 moles per mole of, the compound of the formula (zb )
or. ( n~~ ) or the compound of the general formula (rrnr~) or
(zzzdj or salts thereof. The reaction may be effected usually
at 0 to 150°C, preferably 0 to 70°C, for 5 minutes to 3U
hours.
t7) Phosphorylation
The compounds of the formulas (IVi) . ( zi .) and
(zii~l or salts thereof can be obtained by reacting the
compounds of the formulas (ZVa) , ( za ) and (~ma) or salts
thereof, respectively, with a phosphorylating agent in the
presence or absence of an acid-binding agent.
The solvent which may be used in the reaction may
be any solvent inert to the reaction, and includes,
specifically the same solvents as used in the above-
mentioned sulfonylation. The phosphorylating agent includes,
for example, dialkylphosphoryl halides such as dimethyl-
phosphoryl chloride, diethylphosphoryl chloride,
- 37 -

13~~648
1 dipropylphosphoryl chloride, dibutylphosphoryl chloride
and the like; diarylphosphoryl halides such as diphenyl-
phosphoryl chloride and the like; etc.
The acid-binding agent which may be used in thc~
reaction includes specifically the same acid-binding agents
as used in the above-mentioned sulfonylation. The amount
of the phosphorylating agent used and the amount of the
optionally used acid-binding agent are at least equimolar
to, preferably 1.0 to 1.5 moles per mole of, the compound
of the formula (wa) . ( za ) or (~IIa) or a salt thereof . The
reaction may be effected usually at 0 to 150°C, preferably
0 to 50°C, for 5 minutes to 30 hours.
(8) Azidation
The compound of the formula (zj ) or the compounds
of the formulas (rvj ) and (IIIj) or salts thereof can be
obtained by reacting the compound of the formula ( Ia) or
a salt thereof and the compounds of the formulas (fv~) and
~IIa) or salts thereof, respectively, with an azidating agent
in the presence or absence of an acid-binding agent. The
solvent which may be used in the reaction may be any
solvent inert to the reaction, and includes specifically
the same solvents as used in the above-mentioned sulfonyla-
tion.
Also, the azidating agent includes, for example,
dialkylphosphoryl azides such as diethylphosphoryl azide
and the like; diarylphosphoryl azides such_as diphenyl-
phosphoryl azide and the like; etc. The acid-binding agent
which may be used in the reaction includes specifically
- 38 -

_. :~~~0~%~8
1 the same acid-binding agents as used in the above-mentioned
sulfonylation.
The amount of the azidating agent used and the
amount of the optionally used acid-binding agent are at
least equimolar to, preferably 1.0 to 3.0 moles per mole
of , the compound of the formula (zva) , ( za ) or ~ma) or a
salt thereof. The reaction may be effected usually at 0
to 150°C, preferably 15 to 100°C, for 5 minutes to 30 hours.
(a) Oxidation
The compounds of the formulas ( zg , ) and ( zh
can be produced by reacting the compound of the formula
( ze) with an oxidizing agent under the respective condi-
tions; the compounds of the formulas (IVg) and (IVh) or sa~_ts
thereof can be produced by reacting the compound of the
formula (zve) or a salt thereof with an oxidizing agent
under the respective conditions; and the compounds of the
formulas (ITIg) and (IIIt~ or salts thereof can be produced by
reacting the compound of the formula (tile) with an oxidizing
agent under the respective conditions.
The solvent which may be used in the above
oxidation may be any solvent inert to the reaction, and
includes, for example, aromatic hydrocarbons such as benzene,
toleune, xylene and the like; halogenated hydrocarbons such
as methylene chloride, chloroform, dichloroethane and the
like; ethers such as diethyl ether, tetrahydrofuran,
dioxane and the like; fatty acids such as formic acid,
acetic acid and the like; water; etc. These solvents may
be used in admixture of two or more. The oxidizing agent
- 39 -

13404
1 includes, for example, organic peracids such as performic
acid, peracetic acid, perbenzoic acid, m-chloroperbenzoic
acid and the like; hydrogen peroxide; periodic acid;
sodium metes-periodate; potassium metes-periodate; potassium
permanganate; ozone; etc.
The oxidizing agent which is particularly
preferred to obtain the compound of the formula (zg ) or
the compounds of the formulas (mg) and (tmg) or salts th.ereoF
(sulfoxides) includes organic peracids, sodium meta-
periodate, potassium metes-periodate and the like, and the
amount of the oxidizing agent used is 1.0 to 1.2 moles per
mole of the compound of the formula ( le ) or the compound of
the formula (zve) or (III or a salt thereof .
The oxidizing agent which is particularly
preferred to obtain the compound of the formula (Ih ) or
the compounds of the formulas (wh) and (zzlh) or salts thereof
(sulfone) includes organic peracids, hydrogen peroxide
and the like, and the amount of the oxidizing agent used
is 2.0 to 2.5 moles per mole of the compound of the formula
( ze ) or the compound of the formula (TVe~ or (~me~ or a
salt thereof. The compound of the formula (zg ) or the
compound of the formula (zvg) or (m~ or a salt thereof carp.
be, if necessary, further oxidized into sulfones. These
reactions may be effected usually at 0 to 100°C, preferably
0 to 30°C, for 5 minutes to 30 hours.
(ld The compound of the formula (~II~) or a salt thereof
can be obtained by reacting the compound of the formula
(-tZm) or (mc~ or a salt thereof with an amine of the formula

(X), RZaH, or a salt thereof in the presence or absence of
an acid-binding agent, and also the compound of the formula
(If) or a salt thereof can be obtained by reacting the
compound of the formula (Ib) or (Id) with an amine of the
formula (X) or a salt thereof in the presence or absence of
an acid-binding agent.
The solvent which may be used in the reaction may be
any solvent inert to the reaction, and includes, for
example, aromatic hydrocarbons such as benzene, toluene,
xylene and the like; alcohols such as methanol, ethanol,
n-propyl alcohol, isopropyl alcohol, n-butyl alcohol,
isobutyl alcohol, tert.-butyl alcohol and the like; ethers
such as dioxane, tetrahydrofuran, anisole, diethylene
glycol diethyl ether and the like; ketones such as acetone,
methyl ethyl ketone and the like; nitroalkanes such as
nitromethane, nitroethane and the like; esters such as
methyl acetate, ethyl acetate and the like; nitriles such
as acetonitrile and the like; halogenated hydrocarbons such
as methylene chloride, chloroform, dichloroethane and the
like; amides such as N,N-dimethylformamide,
N,N-dimethylacetamide and the like; sulfoxides such as
dimethylsulfoxide and the like; etc. These solvents may be
used in admixture of two or more. Also, the acid-binding
agent includes specifically the same acid-binding agents as
used in the above-mentioned sulfonylation.
The amount of the amine of the formula (X) or a salt
thereof is preferably 2.0 to 5.0 moles per mole of the
compound of the formula (IIIb) or a salt thereof, the
- 41 -
l~ ~ '~1

1 compound of the formula (rIi~~ or a salt thereof, the
compound of the formula ( Ib ) or the compound of the formula
(zd ) when the acid-binding agent is not used, and it can
be reduced by appropriately using the acid-binding agent
The above reactions may be effected usually at
0 to 150°C, preferably at 0 to 100°C, for 5 minutes to 30
hours.
- 42 -

(11) Ring-closure
In order to obtain the compounds of the formulas (7~a),
(.L~b ) , ( I~c ) , (1Y~ ) , GZYe ) , C1~' ) , (IY'9 ) , (1Y'n ) , (~3T 1 ) a
n d ( 1.~'J )
or salts thereof [hereinafter) referred to as the compounds of
the formula (1~-1) or salts thereof] from the compounds of the
formulas (Za), (Sb), (1c), (rd), (Ie), (If), (Ig), (1h), (Z'I) and
(IJ) or salts thereof [namely) the compounds of the formula (I)
15
25
35
- 43 -

13~~b48
or salts thereof], respectively, the compounds of the formula (I)
or salts thereof may be reacted with acetals of N,N-di-substi-
tuted formamide of the formula (gT):
10
20
30
- 44 -

l3~Ob43
R~ 0 0 ~~-
~-i ~ ~ ~ ~.s Cue- )
~ ~'~ ~ s
~
wherein R3 and R4, which may be the same or different, represent
~ alkyl or cycloalkyl groups, or may be linked to form an alkylene
O-
group which forms a ring together with the -CH\ group; and R5
O-
20
30
- 45 -

and R6, which may be the same or different, represent alkyl
groups or may form a heterocyclic group together with the adJa-
cent nitrogen atom, in the presence or absence of a solvent.
10
20
30
- 46 -

~~4~b43
The acetals of the N,N-di-substituted formamide of the
formula ~~gZ) Include acetals of the conventionally known N,N-di-
substituted formamides) for example, N,N-di-C1-5alkylformamido-
di-C1-5alkylacetals such as N,N-dimethylformamldo-dimethylacetal,
N,N-dimethylformamidodiethylacetai, N,N-dimethylformamido-
dipropylacetal, N,N-dimethylformamido-dibutylacetal, N,N-
dlmethylformamido-dineopentylacetal, N,N-diethylformamido-
dimethylacetal,, N,N-dipropylformamido-dimethylacetal, N,N-
dibutylformamido
15
25
35
- 47 -

.~3~(~~~~
1 dimethylacetal and the like; N,N-di-C1-5alkylformamido-
di-C3_6cycloalkylacetals such as N,N-dimethylformamido-
dicyclohexylacetal and the like; N,N-di-Cl-5alkylformamido-
5- or 6-membereQ cyclic acetals such as 2-dimethylamino-
1,3-dioxolane, 2-dimethylaminotetramethyl-1,3~~ioxol_ane
2-dimethylamino-1,3-dioxane and the like; N-formyl-nitrogen-
containing saturated heterocyclic di-Cl-5alkylacetals
which may contain an oxygen atom in addition to the n:i.tr_~:yen.
atom such as N-dimethoxymethylpyrrolidine, N-dimethoxy-
met)~yl_morpholine, N-dimethoxymethylpiperidine and the :L.zIce;
etc o
20
- 48 -

~.34~b~8
1
The solvent which may be used in the reaction may
be any solvent inert to the reaction, and includes, for exa.m-
ple, aromatic hydrocarbons such as benzene, toluene, xy:Lei,.~
and the like; halogenated hydrocarbons such as methylene
chloride, chloroform, dichloroethane and the like; ethers
such as dioxane, tetrahydrofuran, diethylene glycol dimet.7:~.~~a_
ether and the like; esters such as methyl acetate, ethyl
acetate and the like; ketones such as acetone, methyl ethyl
ketone and the like; nitriles such as acetonitrile and i:he
like; alcohols such as methanol, ethanol and the like;
amides such as N,N-dimethylformamide, N,N-dimethylacetamide
and the like; sulfoxides such as dimethylsulfoxide and the
like; pyridine; etc., and these solvents may be used in
admixture of two or more.
The amount of the acetal of the N,N-di-subst itu.Ned
formamide of the formula ( x~ ) used is at least equimoJ.aa.°
to the compound of the formula ( z ) or a salt thereof , aa~.d
it may be used in excess to serve as a solvent. Also, t:he
reaction may be allowed to proceed smoothly by adding an
acid anhydride such as acetic anhydride or the liken 7=n
this case, the amount of an acid anhydride added is
preferably at least equimolar to, particularly prefex~ab7_y
1 . 0 to 5 . 0 moles per mole of , the compound of the forrnu_l a_
(I ) or a salt thereof. The reaction is usually completed
in 5 minutes to 30 hours at a temperature of 0 to 150°C.
Also, the acetal of the N,N-di-substituted formamide of the
_ 49 _

440043
1 formula (XI ) may be prepared in the reaction system. In
this case, the intermediate compound of the formula ~tII:)
or a salt thereof is formed during the reaction:
O
F CI -C-COORla
/R5 (XII )
N HC-N~R6
R NH
X
F
wherein Rla, R2, R5, R6 and X have the same meanings as
defined above. The above intermediate compound can be
isolated according to the conventional method; however, it
may be converted to the compound of the formula lIV-~)or a
salt thereof without the isolation of the above intermediate.
When the intermediate compound of the formula (XII) or a
salt thereof is isolated, this may be subjected to ring-
closure in the presence or absence of an acid to obtain th.e
compound of the formula (IV-1)or a salt thereof . The solvent
used in this ring-closure may be any solvent inert to the
reaction, and includes, the same as the solvents used in.
the above-mentioned reaction; fatty acids such as formic
acid, acetic acid and the like; water; etc. These may be
used in admixture of two or more. The optionally used acid
includes, for example, mineral acids such as hydrochloric
- 50 -

~~40~4~
1 acid, hydrobromic acid, sulfuric acid and the like; organic
carboxylic acids such as oxalic acid, trifluoroacetic acid
and the like; sulfonic acids such as methanesulfonic acid,
p-toluenesulfonic acid, naphthalenesulfonic acid and the
like; etc., and these may be used usually in an amount at
least equimolar to the compound of the formula III). Said
reaction is effected usually at 0 to 150°C for 5 minutes to
30 hours.
Moreover, the compound of the formula (IV-1) or a
salt thereof can also be produced by reacting a trialkyl_
orthoforate in place of the acetal of the N,N-di-substituted
formamide in the presence or absence of acetic anhydride.
The reaction is effected in the presence or absence of a
solvent, and the solvent may be any solvent inert to the
reaction, and includes, for example, aromatic hydrocarbons
such as benzene, toluene, xylene and the like; ethers such
as dioxane, tetrahydrofuran, diethylene glycol dimethyl
ether, dimethyl Cellosolve and the like; halogenated
hydrocarbons such as methylene chloride, chloroform,
dichloroethane and the like; alcohols such as methanol,
ethanol and the like; esters such as methyl acetate, et?.zyl
acetate and the like; amides such as N,N-dimethylformamide,
N,N-dimethylacetamide and the like; sulfoxides such as
dimethylsulfoxide and the like; etc. These may be used in
admixture of two or more. Also, the trialkyl orthoformates
include trimethyl orthoformate, triethyl orthoformate and
the like, and these may be used as the solvent. The amount
of the orthoformate used is preferably at least equimolar
- 51 -

r l3~Ob4~
to the compound of the formula (I) or a salt thereof. The
reaction may be effected usually at 0 to 150°C, preferably
at 15 to 110°C, for 5 minutes to 30 hours.
(12) Substitution with an amine
In order to produce the compounds of the formula (II)
or salts thereof from the compounds of the formulas (IVd),
(IVe), (IVg), (IVh), (IVi) and (IVj) or salts thereof
hereinafter, referred to as the compounds of the formula
(IV-2) or salts thereof, the compounds of the formulas (IV-
2) or salts thereof may be reacted with an amine of the
formula (X) or a salt thereof in the presence or absence of
an acid-binding agent. The solvent which may be used in
the reaction may be any solvent inert to the reaction, and
includes for example, alcohols such as methanol, ethanol,
n-propyl alcohol, isopropyl alcohol, n-butyl alcohol,
isobutyl alcohol, tert.-butyl alcohol and the like; ethers
such as dioxane, tetrahydrofuran, anisole, diethylene
glycol diethyl ether and the like; ketones such as acetone,
methyl ethyl ketone and the like; nitroalkanes such as
nitromethane, nitroethane and the like; esters such as
methyl acetate, ethyl acetate and the like; nitriles such
as acetonitrile and the like; aromatic hydrocarbons such as
benzene, toluene, xylene and the like; halogenated
hydrocarbons such as methylene chloride, chloroform,
dichloroethane and the like; amides such as
N,N-dimethylformamide, N,N-dimethylacetamide and the like;
sulfoxides such as dimethylsulfoxide and the like; etc.
These may be used in admixture of two or more.
Also, the acid-binding agent includes, for
- 52 -

1 example, organic or inorganic bases such as triethylamine,
diisopropylethylamine, DBU, pyridine, potassium tert.-
butoxide, potassium carbonate, sodium carbonate, sodium
hydride and the like.
The amount of the amine of the formula (x ) or
a salt thereof used is preferably 2.0 to 5.0 moles per mole
of the compounds of the formula (IV-~2) or salts thereof when
the acid-binding agent is not used, and it can be reduced
by appropriately using the acid-binding agent.
The reaction may be effected usually at 0 to
150°C, preferably at 0 to 100°C, for 5 minutes to 30 hours,.
In the above reaction, in the case of the compound
of the formula (~) or a salt thereof, the group of the
formula RlOS03- is preferably a bulky a7_kanesulfonyloxy
or arenesulfonyloxy group, particularly preferably an
arenesulfonyloxy group in which at least one carbon atom
adjacent to the carbon atom to which the oxysulfonyl group
is attached is substituted by the above-mentioned sub-
stituent.
The compound obtained in each of the above-
mentioned steps may be optionally subjected to removal of
protecting group in a known manner to obtain the corre-
sponding free carboxylic acid. Further, the free carboxylic
acid may optionally be subjected to salt-forming reaction
or esterification in a manner known per se to obtain the
corresponding salt or ester.
The compounds obtained by the above-mentioned
reactions may be isolated or separated by a conventional
- 53 -

~3~~~48
1 method, or may be used in the subsequent reactions without
isolation or separation.
The process of this invention is very advantageous
in industry in that the compcund of the formula (jI ) or a
salt thereof can be obtained without via a 2,6-dichloro-
5-fluoropyridine derivative which is an intermediate in the
processes disclosed in the above-mentioned Program and
Abstract of the 24th I.C.A.A.C. and Japanese Patent
Application Kokai (Laid-Open) No. 228,479/85 (said deriva-
tive causes a medical injury such as a rash or the like).
Antibacterial activities of typical compounds
derived from the compounds of this invention are shown below.
Test method
According to the standard method of Japan Society
of Chemotherapy [CHEMOTHERAPY, 29(1), 76-79 (1981)], a
bacterial solution obtained by culturing in F-heart Infusion
broth (manufactured by Eiken Kagaku) at 37°C for 20 hours
was inoculated onto a Heart Infusion agar containing a drug
and cultured at 37°C for 20 hours, after which the growth
of the bacteria was observed to determine the minimum
concentration at which the growth of the baceteria was
inhibited as MIC (ug/ml). The amount of the inoculated
baceteria was 104 cells/plate (106 cells/ml). The MIC
values of the following test compounds are as shown in. TabJ_e
1.
- 54 -

:~3~0~48
Table 1
O
F COON
J~, y
N N ~~ X
NH2-HCl
F
X
Bacteria F H
St. aureus FDA209P X0.05 X0.05
St. equidermidis IID886 50.05 0.1
St. aureus F-137* 50.05 0.1
E. coli NIHJ 50.05 X0.05
E. coli TK-111 50.05 X0.05
E. coli GN5482** <0.05 -_<_0.05
Ps. aeruginosa S-68 0.2 0.2
Aci. anitratus A-6 X0.05 X0.05
Ps. aeruginosa IF03445 0.2 0.2
Ps. aeruginosa GN918** 0.1 O.J..
*: penicillinase-producing bacteria
**: cephalosporinase-producing bacteria
1 When the compound of the formula (zr ) or a salt
thereof is used as a drug or medicine, it is appropriately
combined with carriers which are used in conventiona7_
pharmaceutical preparations, and is prepared into tablets,
capsules, powders, syrups, granules, suppositories,
- 55 -

1 ointments, injections and the like in a conventional manner.
The administration routes, dosage and number of admini-
strations can be appropriately varied depending upon the
symptoms of patients, and it may be usually administered
orally or parenterally (for example, by injection, drip,
administration to rectum) to an adult in an amount of
0.1 to 100 mg/kg/day in one to several portions.
This,invention will be explained below referring
to Examples, which are not by way of limitation but by way
of illustration.
Symbols used in the Examples have the following
meanings:
Me: methyl group, Et: ethyl group,
n-Pr: n-propyl group, i-Pr: isopropyl groupf
Ac: acetyl group
25
56

1 Example
In 7 ml of anhydrous tetrahydrofuran was dissolved
200 mg of 2-(2,4-difluorophenylamino)-5-fluoro-6-methoxy-
nicotinoyl chloride, and 1 ml of an anhydrous tetrahydro-
furan solution containing 45 mg of imidazole and 65 mg of
triethylamine was dropped into the resulting solution at
-20 to -10°C, after which the resulting mixture was subjected
to reaction at room temperature for 30~minutes. Sub-
sequently, 150 mg of magnesium ethoxycarbonylacetate
was added thereto at room temperature, and the resulting
mixture was subjected to reaction under reflux for 30
minutes, after which the reaction mixture was added to a
mixture of 10 ml of ethyl acetate and 10 ml of water. The
pH of the mixture was adjusted to 2.0 with 2 N hydrochloric
acid. The organic layer was separated, and 5 ml of water
was added thereto, after which the pH thereof was adjusted
to 7.5 with saturated aqueous sodium hydrogencarbonate solu-
tion. The organic layer was separated, washed successively
with 5 ml of water and 5 ml of saturated aqueous sodium
chloride solution, and then dried over anhydrous magnesium
sulfate. The solvent was removed by distillation under
reduced pressure, and to the crystalline material thus
obtained was added 1 ml of disiopropyl ether, after which
crystals were collected by filtration to obtain 190 mg
(yield 81.70) of ethyl 2-[2-(2,4-difluorophenylamino)-5-
fluoro-6-methoxynicotinoyl]acetate having a melting point
of 148-149°C.
- 57 -

134Q~~i~~~
Melting point: 149-150°C (recrystallized from
benzene)
I R ( KB r ) cm 1 . v~=o 17 4 5
NMR (CDC13) 8 values:
1.30 (3H, t, J=7Hz), 3.90 (2H, s), 4.02 (3H, s),
4.27 (2H, q, J=7Hz), 6.65-7.35 (2H, m),
7.73 (1H, d, J=lOHz), 7.90-8.40 (1H, m),
11.19 (1H, bs)
Example 2
The same procedure as in Referential Example 16 as
mentioned below and Example 1 was repeated to obtain the
compounds shown in Table 2.
30 - 58 -
__ -~~'~i

13~~~;~~
. . I
'Q N
. ~
x M , x d. s~
N ~ ,x M O
h N r-1 ''' ~ U
.. 1 x -- _
U7 h In Q1 N U1 1
O 61 lD II r-I M
h-> ~
r-I M l0 ~ N ,'I,'
c~$ O N
. . r~j ,.~ . -
~O N N ~ N O
x x x x o, x
h h rl ~ h .
M n n -- n M .
--I h h h . =,
U ~7 x - N
r-I ~r' ~.
U -t.~ ~' ~ .r .t-y o~ -
h I I
o t7 0
~, '~.C~-n .'T'r ~ L(1 ..fir ~r' M
$' M N ~ M ~D ~ UI
z ,. ~ ~ co .r ~ U,
I I
Ul r-1 Ln O h (~ L(l O
O M N x O N ~f7 x M G1
N . . N . .
-L~ rl ~' ~-' ~ r-1 N ~' lD l0
O
O .~
-L~ ~-I r-1
W Q, 1
O
c~a O rl U
U C~ rd O
U II
ai o z -~- w n m~ ~
.-Q .~ ~r h h
.tea '~ r-~ r~
N ~z w
x
H
N
H
~l ) '~ ?Wf
~ C2, O
-r-I N O N .-.
O ~r-I S-1 -ra O
r~ ~ r-~ ~'.,
r-I O r-i N
tr U rt cmn r~ N
o .t~ ~ri
w-1 '--' M U7 ~ r~ O Ul N
~1-~ 01 ~y b ~-. l0
r I I S-I ~-I r~ ~-I
U ~ Ql I U )~
~ ~ O .s~ O N O
N ?-I ~I -t-~ l0 S-I a
Ol v 4-I ~ ri '~ 4-~
I
z3 M
s~ O
~U U~ N
N O
O ~r
U
I
ri
U
- 59 -

13~06~~
I
. ~,
. _. ~, _
x x ~ x +~
M N x N ~ r-1 5~
-- x N -- ~ -- O
' U
m II N ~ o
N h'~ l0 N N I
p
rl ~ ~' O~
. b M I
x O
. . . . ~ N ~
N N x x U1
x ~ ~ x x N N C
f~ '-' lD d' " x ~ tn U7
II ~ ~ -, ~ x M
h a~ ~ ~ II N
N N ~''~ N t'7 '-' I~ N
x ~n ~ x x ~n I x x
av .t1 rd ~-I r-a ~ ~ ~ ~ .>~ o N ~-I
._ II _. ~ ~. ~. II .,~ o, .D ~ --
h . h . ~ a
N x x tf1 O O O x ~ M lD h l0
r~ r--I N N N tn ~I' N r-I x CO
r~ ~.. ,--I x . . ~ . N . r~ ~ ~p ~ (.
00 '-' '-' I~ M ~!' v f~ v GO ~-' v Zf O
I M II I I I 1 t~ N N ~-i
f~ N 01 N 17 ~ p (~ O M O O O 01 x x
tI1 Q1 ~ N l0 C~ O1 M N l0 O ~ N I~ I~ (''~
o . . . . . . . . ,~ ~ II II ~-1
C~ I~ r~ r-I -E-~ N M M l0 f~ f~ ~ ri rl r] t'J "'~
O
U
O O
M M
N I~ I~
r~ r~
r-1
H -
b rd
N O Q.,
N N O
~rl ~-I ~rl ~I
r~i I N r--1 S~
r-I O .~ ~-t O
tf1 (CS U7 ~-1 M (d UJ
~ ~ ~ri ~ O .~~ ~r-i
N U7 -.-i r-I U7 -rI
N ~Jy '1'~ r-I I .fit ~ .~
r-~ ~-I 'Jy In ~1 ~-1
I U ~ p., ~ U ~ N
N O O N N O ,s~
N ~-I S-1 1-I O ~-~ ~-I -d-~
r-1 '--' 4-1 ~ ri '-' 4-I
I
1-~ M S-I
W 0
I
I
I -1~
- 60 -

.~~40~~8
M tI7
x o x . . r,
N . M x ~ -- x
O '-' N ,-!
I v ~ O -r
Q1 CO N N
CO a1 r-i N ~ ~
N ~p . N
M tl1 U7 N ~ - I
x ~ x ,-,
. N (\ . . x M r-I
~ Q1 .r
N N x N I~ N x v ..
x x ~-I x ~ o in x ,.n
r~ -- c~ N . .ra r~ -- r---~--.~
II II II ~ ~ ~ II ~ N
h h N ~ x i~ N ~"~ ~ N x
o I x x x ~ x
.--I -- .+~ n n
~ n h h
t~ ~ h oo M o 00 00
x x - x o, o, x t~ co ~-I M
M N M . . ~ . M . (/] , (~ t~, , r>;'j ,
M '~S O ~-' N ~. V' ...~ ~~ (' ~ CO
1 N r-I I I I I
O ~ ~ x ~ I~ M N M LC1 f~ f~ M O
N N x N M 1~ x ~ N Q1 O M ~p r--I ~' O O
~ . . p ~
r-I ~1' v r-I M ~'] " ~" rW -1 N M M W' l0 I~ N
'L~
S~
O
U
vn o o u1 o
N M V' M I~
N I~ I~ l0 I~ l0
r~ r-I r-1 ,-I r-I
r-I
~, ~ ~ ~ r-1
N N O N
N x ~ N _. N >~ ~
~ ,-.I -r-I ~ -~ ~S
.-1 .~ o r-I s~ rl .c ~-,
r-I r-, I ~ .-I U r-t ,-I -7.-~ o
c1' rti ?, >~ cd N cd ~, N
M -1~ .~ I ?t +~ >~ +.~ .-~ I
r~ Ul -N ~ .l~ r-I Ul N tl~ Ul -~-~ N
I ~ ~ -1.-~ l0 ~f .~ O~ ~y O ~
In ~-I (d r-I r-1 ~-I r-1 ~-1 ~
~ U 1~ -I-~ ~ t U i~ i U ~ +
N N O Q7 O O N O V' ~ O ~ ..
M 5,.1 ~-I U rl lD ~-I S-1 m S~-1 f~-1 U ~-I
r-I '-~ 4..1 (Cf '-' ri v 4-~ r--I ~--~ 4-1 rid ~---
1
z
I
I
z
C z' x z
U U
- 61 -

1 Example 3
In 4 ml of anhydrous tetrahydrofuran was dissolved
200 mg of 1-[2-(2,4-difluorophenylamino)-5-fluoro-6-
(mesitylenesulfonyloxy)nicotinoyl]imidazole, and 90 mg of
magnesium ethoxycarbonylacetate was added thereto, after
which the resulting mixture was subjected to reaction at
50 to 60°C for 20 minutes. Subsequently, the reaction
mixture was added to a mixture of 10 ml of ethyl acetate and
ml of water, and the pH thereof was adjusted to 2.0 with
10 2 N hydrochloric acid. The organic layer was separated,
washed successively with 5 ml of water and 5 ml of saturated
aqueous sodium chloride solution, and then dried over
anhydrous magnesium sulfate. The solvent was removed by
distillation under reduced pressure, and to the crystalline
material thus obtained was added 1 ml of diethyl ether,
after which crystals were collected by filtration to obtain
175 mg (yield 84.20 of ethyl 2-[2-(2,4-difluorophenylamino)-
5-fluoro-6-(mesitylenesulfonyloxy)nicotinoyl]acetate. The
physical properties of this compound were identical with
those of the compound obtained in Example 2 .
In the same manner as above, the following
compounds were obtained.
o Ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-
methoxynicotinoyl]acetate
o Ethyl 2- [ 2- ( 2 , 4-dif luorophenylamino) -6-ethylthio-5~-
fluoronicotionyl]acetate
o Ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-
phenylthionicotinoyl]acetate
- 62 -

~34064~
1 The physycal properties of these compounds were
identical with those of the respective compounds obtained
in Examples 1 and 2 .
Example 4
In 37 ml of anhydrous tetrahydrofuran was suspended
930 mg of 6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluoro-
phenylamino)-5-fluoronicotionic acid, and 760 mg of N,N°-
carbonyl diimidazole was added thereto with ice-cooling,
after which the resulting mixture was subjected to reaction
at room temperature for 12 hours. Subsequently, 670 mg of
magnesium ethoxycarbonylacetate was added to the reaction
mixture, and the resulting mixture was subjected to reaction
at 60°C for 2 hours. The reaction mixture was added to a
mixture of 100 ml of ethyl acetate and 50 ml of water, and
the pH thereof was adjusted to 2.0 with 2 N hydrochloric
acid, after which the organic layer was separated. To the
organic layer was added 50 ml of water and the pH thereof
was adjusted to 7.0 with saturated aqueous sodium hydro-
gencarbonate solution. The organic layer was separated,
washed successively with 50 ml of water and 50 ml of saturat-
ed aqueous sodium chloride solution, and dried over
anhydrous magnesium sulfate. The solvent was removed by
distillation under educed pressure, and the residue thus
obtained was purified by a column chromatography [Wako
Silica Gel C-200, eluant: chloroform-ethanol (200:1 by
volume) to obtain 610 mg (yield 55.70) of ethyl 2-[6-(3-
acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-
- 63 -

I~~O~i~
1 5-fluoronicotionyl]acetate having a melting point of
182-184°C.
Example 5
(1) In 94 ml of anhydrous tetrahydrofuran was suspended
2.34 g of 2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxy-
niconic acid, and 2.00 g of N,N'-carbonyldiimidazole was
added thereto with ice-cooling, after which the resulting
mixture was subjected to reaction at room temperature for 2
hours. Subsequently, 3.50 g of magnesium ethoxycarbonyl-
acetate was added to the reaction mixture, and the mixture
was subjected to reaction under reflux for 1.5 hours, after
which the reaction mixture was added to a mixture of 150 ml
of ethyl acetate and 150 ml of ~-~ater, and the pH of the
mixture was adjusted to 2.0 with 6 N hydrochloric acid. The
organic layer was separated, and washed successively with
80 ml of saturated aqueous sodium hydrogencarbonate solution
and 80 ml of water, after which 80 ml of water was added
thereto and the pH thereof was adjusted to 2.0 with 5 N
hydrochloric acid. The organic layer was separated, washed
successively with 80 ml of water and 80 ml of saturated
aqueous sodium chloride solution, and then dried over
anhydrous magnesium sulfate. The solvent was removed by
distillation under reduced pressure, and to the crystalline
material thus obtained was added 8 ml of diethyl ether, after
which crystals were collected by filtration to obtain 1.93 g
(yield 66.20) of ethyl 2-[2-(2,4-difluorophenylamino)-5-
fluoro-6-hydroxynicotinoyl]acetate having a melting point
- 64 -

l~~Qb4
1 of 161-162°C.
Melting point: 161.5-162°C (recrystallized from
benzene)
IR (KBr) cm 1. vC=~ 1725, 1665
NMR (CDC13) 8 values:
1.29 (3H, t, J=7Hz), 3.74 (2H, s), 4.20 (2H,
q, J=7Hz) , 6.57-7.69 (4H, m) , 10.17 (1H, bs) ,
11.52 (1H, bs)
In the same manner as above, ethyl 2-[5-fluoro-2-
(4-fluorophenylamino)-6-hydroxynicotinoyl]acetate was
obtained.
Melting point: 185°C (decomp.) (recrystallized from
ethyl acetate)
IR (KBr) cm 1. vC=~ 1715, 1685
NMR (CDC13) d values:
1.30 (3H, t, J=7Hz), 3.75 (2H, s), 4.25 (2H, q,
J=7Hz), 7.08-7.34 (4H, m), 7.48 (1H, d, J=llHz),
11.86 (1H, bs)
{2) The same procedure as in (1) above was repeated,
except that the reaction temperature and reaction time were
altered to 60°C and 3 hours, respectively to obtain ethyl
2-[2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinoyl]-
acetate in a yield of 34.5.
Example 6
In 30 ml of anhydrous tetrahydrofuran was
dissolved 700 mg of 6-chloro-2-(2,4-difluorophenylamino)-
- 65 -

1 5-fluoronicotinic acid, and 1.13 g of N,N'-carbonyldi-
imidazole was added thereto with ice-cooling, after which
the resulting mixture was subjected to reaction at room
temperature for 6 hours. Subsequently, 990 mg of magnesium
ethoxycarbonylacetate was added thereto, and the resulting
mixture was subjected to reaction at 55°C for 2 hours, after
~ohich the reaction mixture was added to a mixture of 75 ml
of ethyl acetate and 65 ml of water. The pH thereof was
adjusted to 2.0 with 6 N hydrochloric acid. The organic
layer was separated and 30 ml of water was added, after
which the pH thereof was adjusted to 7.5 with saturated
aqueous sodium hydrogencarbonate solution. The organic layer
was separated, washed successively with 30 ml of water and
30 ml of saturated aqueous sodium chloride solution, and
then dried over anhydrous magnesium sulfate. The solvent
was removed by distillation under reduced pressure, and the
residue thus obtained was purified by a column chromato-
graphy [Wako Silica Gel C-200, eluant: benzene] to obtain
680 mg (yield 78.90) of ethyl 2-[6-chloro-2-(2,4-difluoro-
phenylamino)-5-fluoronicotinoyl]acetate. The physical
properties of this compound were identical with those of the
compound obtained in Example 2 .
In the same manner as above, the following
compounds were obtained:
o Ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-
methoxynicotinoyl]acetate
o Ethyl 2-[2-(2,4-difluorophenylamino)-6-ethylthio-5-
fluoronicotinoyl]acetate
- 66 -

1 o Ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-
phenylthionicotinoyl]acetate
o Ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-(2,4,6-
trimethylbenzenesulfonyloxy)nicotinoyl]acetate
o Ethyl 2-[6-(4-acetyl-1-piperazinyl)-2-(2,4-difluoro-
phenylamino)-5-fluoronicotinoyl]acetate
The physical properties of these compounds were
identical with~those of the respective compounds obtained
in Examples 1 and
Example 7
(1) In 3 ml of methylene chloride was suspended 28U
mg of 2-(2,4-difluorophenylamino)-5-fluoro-6-methoxy-
nicotinic acid, and 580 mg of thionyl chloride and one drop
of N,N-dimethylformamide were added thereto at room
temperature, after which the resulting mixture was sub-
jected to reaction under reflux for 2 hours. The solvent
and the excessive thionyl chloride were removed by distilla-
tion under reduced pressure, and the crystalline material
thus obtained was dissolved in 6 ml of methylene chlorideo
(2) In 6 ml of anhydrous tetrahydrofuran was dissolved
590 mg of diphenylmethyl ethyl malonate, and 90 mg of
sodium hydride (purity: 500) was added at -20°C, after
which the resulting mixture was subjected to reaction at
0 to 10°C for 1 hour. Subsequently, the reaction mixture
was cooled to -20°C, and the methylene chloride solution
obtained in (1) above was dropped thereinto at the same
- 67 -

1 temperature, after which the resulting mixture was subjected
to reaction at -20 to -10°C for 30 minutes. To the reaction
mixture was added 120 mg of acetic acid, and the solvent
was removed by distillation under reduced pressure, after.
which to the residue thus obtained were added 20 ml of
ethyl acetate and 10 ml of water. The pH thereof was
adjusted to 2.0 with 2 N hydrochloric acid. The organic
layer was separated, washed successively with 10 ml of water
and 10 ml of saturated aqueous sodium chloride solution,
and then dried over anhydrous magnesium sulfate. The
solvent was removed by distillation under reduced pressureP
and to the residue thus obtained was added 5 ml of diiso-
propyl ether, after which crystals were collected by
filtration to obtain 430 mg (yield 79. 2 0) of diphenylmethyl
ethyl 2-(2,4-difluorophenylamino)-S-fluoro-6-methoxy-
nicotinoylmalonate.
Melting point: 130-131°C (recrystallized from benzene-
n-hexane (10:1 by volume))
IR (KBr) cm 1. vC=0 1740, 1730(sh)
NMR (CDC13) S values:
1..24 (3H, t, J=7Hz) , 3.94 (3H, s) ,
4.28 (2H, q, J=7Hz) , 5.14 (1H, s) ,
6.40-7.64 (14H, m) , 7.70-8.20 (lII, m) ,
11.10 (1H, bs)
(3) In 2 ml of anisole was dissolved 200 mg of
diphenylmethyl ethyl 2-(2,4-difluorophenylamino)-5-fluoro-
6-methoxynicotinoylmalonate, and 2 ml of trifluoroacetic
- 68 -

~34Q~~~
1 acid was added thereto with ice-cooling, after which the
resulting mixture was subjected to reaction at the same
temperature for 10 minutes. The solvent was removed by
distillation under reduced pressure, and to the crystalline
material thus obtained was added 2 ml of diisopropyl etherP
after which crystals were collected by filtration to obtain
120 mg (yield 94.3%) of ethyl 2-[2-(2,4-difluorophenyl-
amino)-5-fluoro-6-methoxynicotinoyl]acetate.
The physical properties of this compound were
identical with those of the compound obtained in Example 1 .
Example 8
In 2 ml of ethyl acetate was dissolved 100 mg of
ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxy-
nicotinoyl]acetate, and a diethyl ether solution containing
15 mg of diazomethane was added thereto with ice-cooling,
after which the resulting mixture was subjected to reaction
at room temperature for 30 minutes. Subsequently, acetic
acid was added to the reaction mixture until foaming was
not caused in the reaction mixture. The solvent was then
removed by distillation under reduced pressure and to the
crystalline material thus obtained was added 2 ml of
diisopropyl ether, after which crystals were collected by
filtration to obtain 80 mg (yield 77.0%) of ethyl 2-[2-(2,4-
difluorophenylamino)-5-fluoro-6-methoxynicotinoyl]acetate.
The physical properties of this compound were identical
with those of the compound obtained in Example ~. .
- 6q -

~340a4~
1 Example 9
In 4 ml of methylene chloride was dissolved 400 mg
of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxy-
nicotinoyl]acetate, and 300 mg of 2,4,6-trimethylbenzene-
sulfonyl chloride and 150 mg of triethylamine were added
thereto with ice-cooling, after which the resulting mixture
was subjected to reaction at room temperature for 2 hours.
Subsequently, to the reaction mixture were added 4 ml of
methylene chloride and 4 ml of water, and the organic layer
was separa-ted, washed successively with 4 ml of water and
4 ml of saturated aqueous sodium chloride solution, and
then dried over anhydrous magnesium sulfate. The solvent
was removed by distillation under reduced pressure, and to
the crystalline material thus obtained was added 2 ml of
diethyl ether, after which crystals were collected by
filtration to obtain 520 mg (yield 85.80) of ethyl 2-[2-
(2,4-difluorophenylamino)-5-fluoro-6-(2,4,6-trimethyl-
benzenesulfonyloxy)nicotinoyl]acetate. The physical
properties of this compound were identical with those of the
2.0 compound obtained in Example 2 .
In the same manner as above, the following
compounds were obtained:
o Ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-
methanesulfonyloxynicotinoyl]acetate
Melting point: 98-99°C (recrystallized from benzene)
IR (KBr) cm 1. vC=~ 1730
NvIR (CDC13) d values:
1.27 (3H, t, J=7Hz) , 3.28 (3H, s) , 3.93 (2H, s) ,
_ 7~ -

1 4.23 (2H, q, J=7Hz), 6.63-7.43 (2H, m),
7.70-8.23 (m) 10.78 (1H, bs)
(2H) .
7.97 (d, J=9Hz)
o Ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-
(2,4,6-triisopropylbenzenesulfonyloxy)nicotinoyl]-
acetate.
The physical properties of this compound were
identical with those of the compound obtained in Example
Example to
In 1.5 ml of N,N-dimethylformamide was dissolved
150 mg of ethyl 2- [6-chloro-2- ( 2 , 4-di:Eluorophenylamino) -
5-fluoronicotinoyl]acetate, and 70 mg of thiophenol and
60 mg of triethylamine were added thereto, after which the
resulting mi:~ture was subjected to reaction at room tempera-
ture for 1 hour. Subsequently,. to the reaction mixture
were added 20 ml of ethyl acetate and 10 ml of water, and
the pH thereof was adjusted to 2.0 with 2 N hydrochloric
acid. The organic layer was separated, washed successively
with 10 ml of water and 10 ml of saturated aqueous sodium
chloride solution, and then dried over anhydrous magnesium
sulfate. The solvent was removed by distillation under
reduced pressure, and to the crystalline material thus
obtained was added 5 ml of n-hexane, after which crystals
were collected by filtration to obtain 170 mg (yield 94.6%)
of ethyl 2- [2- (2, 4-difluorophenylamino) -5-fluoro-6-pi~.~ny1-
thionicotinoyl]acetate. The physical properties of this
- 71 -

~3~~Q~~~
1 compound were identical with those of the compound obtained
in Example 2 .
Example 11
In 1 ml of N,N-dimethylformamide was dissolved
100 mg of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-
(2,4,6-trimethylbenzenesulfonyloxy)nicotinoyl]acetate, and
17 mg of ethanethiol and 28 mg of triethylamine were added
thereto, after which the resulting mixture was subjected
to reaction at room temperature for 4 hours. Subsequently,
to the reaction mixture were added 3 ml of ethyl acetate
and 3 ml of water, and the pH thereof was adjusted to 1.0
with 2 N hydrochloric acid. The organic layer was separated,
washed successively with 2 ml of water and 2 ml of :saturated
aqueous sodium chloride solution, and then dried over
anhydrous magnesium sulfate. The solvent was removed by
distillation under reduced pressure, and the residue thus
obtained was purified by a column chromatography [Wako
Silica Gel C-200, eluant: benzene-n-hexane (1:2 by volume)]
to obtain 50 mg (yield 67.4%) of ethyl 2-[2-(2,4-difluoro-
phenylamino)-6-ethylthio-5-fluoronicotinoylJacetate. The
physical properties of this compound were identical with
those of the compound obtained in Example2 ,
In the same manner as above, ethyl 2-[2-(2,4-
difluorophenylamino)-5-fluoro-6-phenylthionicotinoyl]-
acetate. The physical properties of this compound were
identical with those of the compound obtained in Example 2 .
- 72

i~~oo~
1 Example 12
In 5 ml of chloroform was dissolved 500 mg of
ethyl 2-[6-chloro-2-(2,4-difluorophenylamino)-5-fluoro-
nicotinoyl]acetate, and 260 mg of 3-aminopyrrolidine
dihydrochloride and 500 mg of triethylamine were added
thereto, after which the resulting mixture was subjected to
reaction under reflux for 1.5 hours. Subsequently, the
reaction mixture was added to a mixture of 5 ml of chloro-
form and 5 ml of water, and the organic layer was separated,
washed successively with 5 ml of water and 5 ml of saturated
aqueous sodium chloride solution, and then dried over
anhydrous magnesium sulfate. The solvent was removed by
distillation under reduced pressure, and to the crystalline
material thus obtained was added 2 ml of diisopropyl ether,
after which crystals were collected by filtration to obtain
480 mg (yield 84.7g) of ethyl 2-[6-(3-amino-1-pyrrolidinyl)-
2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]acetate
having a melting point of 140-142°C.
IR (KBr) cm 1. vC=O 1730
NMR (DMSO-d6) b values:
1.22 (3H, t, J=7Hz), 1.50-2.30 (2H, m),
3.30-4.40 (9H, m), 6.80-7.60 (2H, m),
7.81 (1H, d, J=l4Hz), 8.00-8.70 (1H, m),
11.45 (1H, bs)
Example 13
In 1.5 ml of ethanol was dissolved 140 mg of
anhydrous piperazine, and to the resulting solution was
_ 73 -

~~~o~~~
1 added 150 mg of ethyl 2-[6-chloro-2-(2,4-difluorophenyl
amino)-5-fluoronicotionyl]acetate in portions, and the
resulting mixture was subjected to reaction at room
temperature for 30 minutes. Subsequently, the reaction
mixture was added to a mixture of 5 ml of chloroform and
5 ml of water, and the organic layer was separated, washed
successively with 3 ml of water and 3 ml of saturated
aqueous sodium chloride solution, and then dried over
anhydrous magnesium sulfate. The solvent was removed by
distillation under reduced pressure, and to the crystalline
material thus obtained was added 2 ml of n-hexane, after
which crystals were collected by filtration to obtain 70 mg
(yield 41.2%) of ethyl 2-[2-(2,4-difluorophenylamino)-5-
fluoro-6-(1-piperazinyl)nicotinoyl]acetate.
Melting point: 121-123°C (recrystallized from ethyl
acetate-n-hexane (10:1 by volume))
IR (KBr) cm 1. vC=~ 1745, 1730 (sh)
NMR (CDC13) d values:
1.30 (3H, t, J=7Hz), 2.76-3.10 (4H, m),
3.55-4.00 (6H, m), 4.21 (2H, q, J=7Hz),
6.40-7.20 (2H, m), 7.47 (1H, d, J=l4Hz),
7.75-8.35 (1H, m) , 11.10 (1H, bs)
Example 14
In 1.5 ml of chloroform was suspended 50 mg of
3-aminopyrrolidine dihydrochloride, and 110 mg of triethyl-
amine was added thereto after which the resulting mixture
was subjected to reaction at room temperature for 10
- 74 -

I3~Q~4
1 minutes. Thereafter, 150 mg of ethyl 2-[2-(2,4-difluoro-
phenylamino)-5-fluoro-6-(2,4,6-trimethylbenzenesulfonyloxy)-
nicotionyl]acetate was added thereto, and the resulting
mixture was subjected to reaction at room temperature for
1.5 hours. Subsequently, to the reaction mixture were
added 5 ml of chloroform and 5 ml of water, and the organic
layer was separated, washed successively with 5 ml of water
and 5 ml of saturated aqueous sodium chloride solution,
and then dried over anhydrous magnesium sulfate. The
solvent was removed by distillation under reduced pressures
and to the crystalline material thus obtained was added 2 ml
of diisopropyl ether, after which crystals were collected by
filtration to obtain 110 mg (yield 93.2x) of ethyl 2-[6-
(3-amino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-
fluoronicotionyl]acetate. The physical properties of this
compound were identical with those of the compound obtained
in Example 12 .
Example 15
In 2 ml of methylene chloride was dissolved 130
mg of anhydrous piperazine, and 200 mg of ethyl 2-[2-(2,4-
difluorophenylamino)-5-fluoro-6-(2,4,6-trimethylbenzene-
sulfonyloxy)nicotinoyl]acetate was added thereto with ice-
cooling, after which the resulting mixture was subjected
to reaction at the same temperature for 40 minutes.
Subsequently, the reaction mixture was added to a mixture
of 10 ml of ethyl acetate and 1G ml of water, and the
organic layer was separated, washed successively with 2 ml
- 75 -

134~~4~
1 of saturated aqueous sodium hydrogencarbonate solution and
2 ml of saturated aqueous sodium chloride solution, and
then dried over anhydrous magnesium sulfate. The solvent
was removed by distillation under reduced pressure, and to
the crystalline material thus obtained was added 1 ml of
n-hexane, after which crystals were collected by filtration
to obtain 110 mg (yield 69.90 of ethyl 2-[2-(2,4-difluoro-
phenylamino)-5-fluoro-6-(1-piperazinyl)nicotinoyl]acetate.
The physical properties of this compound were identical
with those of the compound obtained in Example 13 .
Example 16
In 1 ml of chloroform was dissolved 100 mg of
ethyl 2-[6-(3-amino-1-pyrroldinyl)-2-(2,4-difluorophen.yl-
amino)-5-fluoronicotinoyl]acetate, and 26 mg of acetic
J.5 anhydride was added thereto, after which the resulting
mixture was subjected to reaction at room temperature for
30 minutes. Subsequently, the reaction mixture was added
to a mixture of 1 ml of water and 1 ml of chloroform, and
the organic layer was separated, washed successively with
1 ml of water and 1 ml of saturated aqueous sodium chloride
solution and then dried over anhydrous magnesium sulfate.
The solvent was removed by distillation under reduced
pressure, and to the crystalline material thus obtained was
added 0.5 ml of diisopropyl ether, after which crystals
were collected by filtration to obtain 80 mg (yield 72.8%)
of ethyl 2-[6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-
difluorophenylamino)-5-fluoronicotinoyl]acetate. The
- 76 -

~.~40~~~
1 physical properties of this compound were identical with
those of the compound obtained in Example z .
In the same manner as above, ethyl 2-[6-{4-
acetyl-1-piperazinyl)-2-(2,4-difluorophenylamino)-5-
fluoronicotinoyl]acetate was obtained. The physical Pro-
perties of this compound were identical with those of the
compound obtained in Example 2 .
Example 17
In 58 ml of N,N-dimethylformamide was dissolved
5.80 g of ethyl 2-[2-{2,4-difluorophenylamino)-5-fluoro-6-
(2,4,6-triisopropylbenzenesulfonyloxy)nicotinoyl]acetate,
and 1.24 g of thiophenol and 1.23 g of triethylamine were
added thereto, after which the resulting mixture was
subjected to reaction at room temperature for 4 hours.
Subsequently, to the reaction mixture were added 400 ml of
ethyl acetate and 200 ml of water, and the pH thereof was
adjusted to 2.0 with 2 N hydrochloric acid. The organic
layer was separated, washed successively with 200 ml of
water and 200 ml of saturated aqueous sodium chloride solu-
tion, and then dried over anhydrous magnesium sulfate. The
solvent was removed by distillation under reduced pressure,
and to the crystalline material thus obtained was added
50 ml of n-hexane, after which crystals were collected by
filtration to obtain 3.99 g (yield 95.6°x) of ethyl
2-[2-(2,4-difluorophenylamino)-5-fluoro-6-phenylthio-
nicotinoyl]acetate. The physical properties of this compound
were identical with those of the compound obtained in
_ 77 _

-~~~Qb~
1 Example
In the same manner as above, ethyl 2-[2-(2,4-
difluorophenylamino)-6-ethylthio-5-fluoronicotinoylJacetate
was obtained. The physical properties of this compound
were identical with those of the compound obtained in
Example 2 .
Example 18
In 10 ml of anhydrous acetonitrile was suspended
1.00 g of ethyl 2-(2-(2,4-difluorophenylamino)-5-fluoro-6-
hydroxynicotinoyl]acetate, and 390 mg of triethylamine and
670 mg of diethylphosphoryl chloride were added thereto
with ice-cooling, after which the resulting mixture was
subjected to reaction at room temperature for 1.5 hours.
To this reaction mixture were added 50 ml of methylene
chloride and 50 ml of water, and the organic layer was
separated, washed with four 50-ml portions of water, and
then dried over anhydrous magnesium sulfate. The solvent=
was removed by distillation under reduced pressure, and to
the residue thus obtained was added 15 ml of n-hexane, after
which the crystals thus deposited were collected by filtra~-
tion to obtain 1.26 g (yield 9l.Oo) of ethyl 2-[6-diethoxy-
phosphinyloxy-2-(2,4-difluorophenylamino)-5-fluoro-
nicotinoyl]acetate having a melting point of 127-130°C.
Melting point: 131.5-133°C (recrystallized from
benzene)
IR (KBr) cm 1. vC-~ 1740
NMR (CDC13) 8 values:
- 78 _

:L3~O~i~ 3
1 1.30 (3F-I, t, J=7Hz) , 1.33 (3H, t, J=7I3z) ,
1.35 (3H, t, J=7Hz) , 3.95 (2H, s)
4.15 (2H, q, J=7Hz), 4.25 (2H, q, J=7Hz),
4.30 (2H, q, J=7Hz), 6.65-7.35 (2H, m),
7.96 (1H, d, J=9Hz), 8.15-8.75 (1H, m),
11.05 (1H, bs)
In the same manner as above,.ethyl 2-[2-(2,4-
difluorophenylamino)-6-diphenoxyphosphinyloxy-5-fluoro-
nicotinoyl]acetate was obtained.
Melting point: 85-86°C (recrystallized from diethyl
ether)
IR (KBr) cm 1. vC=~ 1740
iVbIR (CDC13) S values:
1.25 (3H, t, J=7Hz), 3.90 (2H, s),
4.20 (2H, q, J=7Hz), 6.30-7.60 (m)
(12H) ,
7.22 (bs)
7.75-8.55 (2F3, m) , 11.07 (1H, bs)
Example 19
In 14 ml of methylene chloride was dissolved
1.40 g of ethyl 2-[2-(2,4-difluorophenylamino)-6-etlnylth-io-
5-fluoronicotinoyl]acetate, and 1.59 g of m-chloroperbenzoic
acid (purity: 80g) was added thereto with ice-cooling,
after which the resulting mixture was subjected to .reaction
at room temperature for 3 hours. The precipitates were
removed by filtration, and then, 10 ml of water was added
to the filtrate thus obtained, after which the pH thereof
- 79 -

1 was adjusted to 7.5 with saturated aqueous sodium hydro-
gencarbonate solution. The organic layer was separated,
washed successively with 10 ml of water and 10 ml of
saturated saqueous sodium chloride solution, and then dried
over anhydrous magnesium sulfate. The solvent was removed
by distillation under reduced pressure, and to the residue
thus obtained was added 10 ml of diethyl ether, after which
the crystals thus deposited were collected by filtration to
obtain 1.28 g (yield 84.6%) of ethyl 2-[2-(2,4-difluoro-
phenylamino)-6-ethanesulfonyl-5-fluoronicotinoyl]acetate
having a melting point of 113-114.5°C.
Melting point: 114-115°C (recrystallized from
diisopropyl ether)
IR (KBr) cm 1. vC=~ 1740
NMR (CDC13) d values:
1.24 (3H, t, J=7Hz), 1.27 (3H, t, J=7Hz),
3.27 (2H, q, J=7Hz), 4.00 (2H, s),
4.18 (2H, q, J=7Hz), 6.55-7.10 (2H, m),
7. 70-8 .30 (m) 10. 60 (1H, bs) ,
(2H) ,
8.03 (d, J=9Hz)
In the same manner as above, ethyl 2-[6-benzene-
sulfonyl-2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]-
acetate was obtained.
Melting point: 140-141°C (recrystallized from ethyl
acetate)
IR (KBr) cm 1 vC=~ 1740
NMR (CDC13) d values:
- 80 -

1 1.27 (3H, t, J=7Hz), 4.01 (2H, s),
4.21 (2H, q, J=7Hz), 6.40-7.00 (2H, m),
7.20-8.20 (m) 10.72 (1H, bs)
(7H) .
8.02 (d, J=9Hz)
Example 20
In 20 ml of methylene chloride was dissolved 2.0
g of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-
phenylthionicotinoyl]acetate, and 1.01 g of m-chloro-
perbenzoic acid (purity: 80%) was added thereto with ice-
cooling, after which the resulting mixture was subjected to
reaction at the same temperature for 5 hours. Subsequently,
the precipitates were removed by filtration, and 20 ml of
water was added to the filtrate thus obtained, after which
the pH thereof was adjusted to 7.5 with saturated aqueous
sodium hydrogencarbonate solution. The organic layer was
separated, washed with 20 ml of water, and then dried over
anhydrous magnesium sulfate. The solvent was removed by
distillation under reduced pressure, and the residue thus
obtained was purified by a column chromatography [Wako Silica
Gel C-200, eluant: benzene-ethyl acetate (50:1 by volume)]
to obtain 1.39 g (yield 67.1%) of ethyl 2-[6-benzenesulfinyl-
2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]acetate
having a melting point of 105-106.5°C.
Melting point: 107-107.5°C (recrystallized from
diisopropyl ether)
IR (KBr) cm 1. vC=~ 1730
NMR (CDC13) d values:
- 81 -

I3~0643
1 1.25 (3H, t, J=7Hz) , 3.97 (2Ii, s) ,
4. 21 (2H, q, J=7F-iz) , 6.60-8.00 (8H, m) ,
8.30-8 .85 (1H, m) , 10. 90 (1H, bs)
In the sarne manner as above, ethyl 2- f.2w- ( 2, 4--
difluorophenylamino) - .6-ethanesulf inyl-5-fluoron..~.cot:in'o~rL,~ -
acetate was obtained.
rlelting point,: 115-116°C (recrystallized from diiso-
pr.opy.)- et-.her. ) .
IR (KBr) cm 1. vC=o 1735
NMR (CDC13) d values:
1.29 (3H, t, J=7Hz) , 1.31 (3H, t, J='ZHz)
3.08 (2H, q, J=7FIz) , 4.03. (2H, s) ,
4.23 (2H, q, J=7Hz) , 6.65-7.15 (2II, m) ,
7.97 (1H, d, J=9Hz) , 8.40-9.00 (1H, yn)
10.88 (1H, bs)
Example 21
In 10 ml of anhydrous acetonitrile was srz:~pendec~.
1.05 g of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-
hydroxynicotinoylJacetate, and 450 mg of triethylamine and
1.22 g of diphenylphosphoryl azide were added thereto wa:itl-r
ice-cooling, after which the resulting mixture was subjected
to reaction at room temperature for 4 hours. To this
reaction mixture were added 50 ml of ethyl acetate and
50 ml of water, and the organic layer was separated, and
then dried over anhydrous magnesium sulfate. The solvent
was removed by ditillation under reduced pressures and the
82 -

~.3~U~43
1 residue thus obtained was purified by a column chromoato-
graphy [Wako Silica Gel C-200, eluant: benzene] to obtain
550 mg (yield 48.90) of ethyl 2-[6-azido-2-(2,4-difluoro-
phenylamino)-5-fluoronicotinoyl]acetate having a melting
point of 130-131°C.
Melting point: 130.5-131.5°C (recrystallized from
benzene)
IR (KBr) cm 1. vN 2130, vC=~ 1750
3
NMR (CDC13) 8 values:
1.29 (3H, t, J=7Hz), 3.92 (2H, s),
4.25 (2H, q, J=7Hz), 6.60-8.45 (4H, m),
10.94 (1H, bs)
20
- 83 -

.-_ ~ - ~3~0~4~
Referential Example 1
(1) In a 300 ml of ethyl acetate were suspended 50 g
of ethyl ~i-imino-(3-phenoxypropionate hydrochloride and 27.8
g of 2,4-difluoroaniline, and the resulting suspension was
subjected to reaction under reflux for 2 hours. The
deposited crystals were separated by filtration and washed
with two 200-ml portions of ethyl acetate to obtain 47 g
(yield 82.20 of ethyl N-(2,4-difluorophenyl)amidinoacetate
hydrochloride having a melting point of 196-197°C.
IR (KBr) cm-1: v~-01730
NMR (DMSO-d6) 8 values:
1.26 (3H, t, J=7Hz), 4.07 (2H, s),
30 - 84 -
;.
:_ ~:

~.340~43
1 4.19 (2H, q, J=7Hz), 7.02-7.78 (3H, m),
9.11 (1H, bs) , 10.26 (1H, bs) , 12.28 (1H, bs)
In the same manner as above, the following com-
pounds were obtained:
o Methyl N-(2,4-difluorophenyl)amidinoacetate hydro-
chloride
Melting point: 192-193°C
IR (KBr) cm 1. vC=O 1735
NMR (DMSO-d6) d values:
3.74 (3H, s) , 4.09 (2H, s) , 6.91-7.73 (3H, m) ,
9.15 (1H, bs), 10.31 (1H, bs), 12.29 (1H, bs)
o Methyl N-(4-fluorophenyl)amidinoacetate hydrochloride
Melting point: 134-135°C
IR (KBr) cm 1. vC=O 1730
NMR (DMSO-d6) d values:
3.74 (3H, s), 4.05 (2H, s), 7.01-7.59 (4Fi, m),
8.96 (1H, bs), 10.06 (1H, bs), 12.26 (1H, bs)
(2) In a mixture of 92 ml of water and 92 ml of
methylene chloride was dissolved 23.0 g of methyl N-(2,4-
difluorophenyl)amidinoacetate hydrochloride, and the pI-F of
the solution was adjusted to 13 with 2 N aqueous sodium
hydroxide solution. Subsequently, the organic layer was
separated, washed successively with 50 ml of water and. 50 anl..
of saturated aqueous sodium chloride solution and dried
over anhydrous magnesium sulfate. To this solution was
added 27.1 g of the sodium salt of ethyl a-formyl-a-
fluoroacetate at room temperature, and the resulting mixture
- 85 -

was subjected to reaction under reflux for 4 hours, after
which the solvent was removed by distillation under reduced
pressure. To the residue thus obtained were added 92 ml of
water and 46 ml of ethyl acetate, and the crystals thus
deposited were collected by filtration. The crystals thus
obtained were suspended in 184 ml of water and the pH of
the suspension was adjusted to 1.0 with 6 N hydrochloric
acid, and to the crystalline material thus obtained were
added 46 ml of water and 46 ml of isopropyl alcohol, after
which the crystals were collected by filtration to obtain
15.0 g (yield 57.90) of methyl 2-(2,4-difluorophenylamino)-
5-fluoro-6-hydroxynicotinate having a melting point of 222-
223°C.
Melting point: 222-223°C (recrystallized from ethyl
acetate)
IR (KBr) cm 1: v~-01700
NMR (TFA-dl) b values:
4 . 0 6 ( 3H, s ) , 6 . 71-7 . 65 ( 3H, m) , 8 . 12 ( 1H, d,
J=llHz )
In the same manner as above, the following compounds
were obtained:
O Ethyl 2-(2,4-difluorophenylamino)-5-fluoro-6-
hydroxynicotinate
Melting point: 177-178°C (recrystallized from ethyl
acetate)
IR (KBr) cm-1: v~=01700
NMR (TFA-dl) 8 values:
- 86 -
~<
.,,

~~~Qb~~
1 1.52 (3H, t, J=7Hz) , 4.50 (2Ii, q, J=7Hz) ,
6.80-7.65 (3Ii, m) , 8.15 (1H, d, J=llHz)
o Methyl 5-fluoro-2-(4-fluorophenylamino)-6-hydroxy-
nicotinate
Melting point: 227-228°C (recrystallized from ethyl
acetate)
IR (KBr) cm 1. vC=p 1690
NMR (TFA-d~l) d values:
4.05 (3H, s) , 6.89-7.53 (4H, m) ,
8.11 (1H, d, J=llHz)
(3) In a mixture of 5 ml of water and 5 ml of methylene
chloride was dissolved 500 mg of methyl N-(2,4-difluoro-
phenyl)amidino acetate hydrochloride, and the pH of the
resulting solution was adjusted to 13.0 with 2 N aqueous
sodium hydroxide solution. The organic layer was separated
and washed successively with 3 ml of water and 3 ml of
saturated aqueous sodium chloride solution, and then dried
over anhydrous magnesium sulfate. To this solution was
added 820 mg of ethyl 3-(4-methylbenzenesulfonyloxy)-2-
fluoroacrylate, and then, 120 mg of sodium methoxide
(purity: 92.30 and 5 ml of methanol were added thereto at
room temperature, after which the resulting mixture was
subjected to reaction at the same temperature for 24 hours.
The solvent was then removed by distillation under reduced
pressure, and to the residue thus obtained were added 10 m1
of water and 2 ml of ethyl acetate. The pH of the resulting
solution was adjusted to 1.0 with 6 N hydrochloric acid,
_ 87 -

~3!~0~~~
1 and the crystals thus deposited were collected by filtration
and washed successively with 2 ml of water and 2 ml of
isopropyl alcohol to obtain 370 mg (yield 65.70) of methyl
2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinate.
The physical properties of this compound were identical
with those of the compound obtained in (2) above.
(4) The same procedure as in (3) above was repeated,
except that one of the 3-substituted-2-fluoroacrylates shown
in Table 2 was substituted for the ethyl 3-(4-methylbenzene-
sulfonyloxy)-2-fluoroacrylate to obtain the results shown in
Table 3..
Table 3
H
~ C=C-COOEt, NaOMe
Z ~ F F COOMe
F Q NHCCFi2COOMe
II HO NH
F NH F
0
F
Compound Yield
Z ( o)
MeS03- 41.7
O
(~O) 2P0- 50. 7
~
O
CO- 4 4 . 4
- 88 -

1.3~0~~~
1 The physical properties of the compounds obtained
in the respective cases were identical with those of the
compound obtained in (2) above.
Referential Example 2
In 6 ml of tetrahydrofuran was dissolved 200 mg
of methyl 2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxy-
nicotinate, and a solution of about 40 mg of diazomethane
in diethyl ether was added to the resulting solution with
ice-cooling, after which the resulting mixture was subjected
to reaction at room temperature for 30 minutes. Subsequent-
ly, acetic acid was added until foaming was not caused in
the reaction mixture, after which the solvent was removed
by distillation under reduced pressure. The crystals thus
obtained were washed with 6 ml of isopropyl alcohol to
obtain 150 mg (yield 71.6%) of methyl 2-(2,4-difluoro--
phenylamino)-5-fluoro-6-methoxynicotinate having a melting
point of 160-161°C.
Melting point: 160.5-161.5°C (recrystallized from ethyl
acetate)
IR (KBr) cm 1. vC=o 1690
NMR (CDC13) a values:
3.89 (3H, s) , 3.98 (3H, s) , 6.57-7.08 (2H, m) ,
7.81 (1H, d, J=llHz), 8.10-8.97 (1H, m),
10.24 (1H, bs)
~ 5 Referential Example 3
In 5 ml of N,N-dimethylformamide was dissolved
- 89 -

.w 134~~4~
1 200 mg of methyl 2-(2,4-difluorophenylamino)-5-fluoro-6-
hydroxynicotinate, and to the resulting solution were added
110 mg of potassium carbonate and 93 mg of dimethyl sulfate
at room temperature, after which the resulting mixture was
subjected to reaction at the same temperature for 2 hours.
Subsequently, 20 ml of water and 20 ml of ethyl acetate
were added to the reaction mixture, and the organic layer
was then separated, washed successively with 10 ml of water
and 10 ml of saturated aqueous sodium chloride solution,
and thereafter dried over anhydrous magnesium sulfate. The
solvent was removed by distillation under reduced pressure6
and to the crystalline material thus obtained was added
5 ml of isopropyl alcohol, after which crystals were
collected by filtration to obtain 180 mg (yield 86.0°x) o.f
methyl 2-(2,4-difluorophenylamino)-5-fluoro-6-methoxy-
nicotinate. The physical properties of this compound were
identical with those of the compound obtained in Referential
Example 2.
Referential Example 4
In 5 ml of N,N-dimethylformamide was dissolved
200 mg of methyl 2-(2,4-difluorophenylamino)-5-fluoro-6-
hydroxynicotinate, and thereto were added 110 mg of
potassium carbonate and 0.11 g of methyl iodide at room
temperature, after which the resulting mixture was subjected
to reaction at the same temperature for 1 hour. To the
reaction mixture were added 20 ml of water and 20 ml of
ethyl acetate, and the organic layer was separated, washed
successively with 10 ml of water and 10 ml of saturated
- 90 -

' .
1 aqueous sodium chloride solution, and then dried over
anhydrous magnesium sulfate. The solvent was removed by
distillation under reduced pressure and then to the
crystalline material thus obtained was added 5 ml of
isopropyl alcohol, after which crystals were collected-by~
filtration to obtain 190 mg (yield 90.7$) of methyl 2-
(2,4-difluorophenylamino)-5-fluoro-6-methoxynicotinate.
The physical properties of this compound were identical with
those of the compound obtained in Referential Example 2.
Referential Example 5
A mixture of 9.5 g of methyl 2-(2,4-difluoro-
phenylamino)-5-fluoro-6-hydroxynicotinate, 26.5 g of
phosphorus pentachloride and 46.9 g of phosphorus oxychloride
was subjected to reaction at 70-80°C for 4 hours.
Subsequently, the reaction mixture was gradually added to
285 ml of water, and the crystals thus deposited were
collected by filtration and then washed with 57 ml of water.
The crystals thus obtained were purified by a column
chromatography [Wako Silica Gel C-200, eluant: toluene] to
obtain 3.5 g (yield 34.70 of methyl 6-chloro-2-(2f.4-
difluorophenylamino)-5-fluoronicotinate having a meli:ing
point of 137-139°C.
Melting point: 139.5-140.5°C (recrystallized from
diisopropyl ether)
IR (KBr) cm 1. ~C-0 1695
NMR (CDC13) d values:
3.93 (3H, S), 6.61-7.06 (2H, m),
_ 91 -

13~Q~4
1 7.94 (1H, d, J=9Hz), 8.15-8.57 (1H, m),
10.13 (1H, bs)
Referential Example 6
In 10 ml of methylene chloride was suspended
500 mg of methyl 2-(2,4-difluorophenylamino)-5-fluoro-6-
hydroxynicotinate, and to the resulting suspension were
added 440 mg of 2,4,6-trimethylbenzenesulfonyl chloride anc~
220 mg of triethylamine, after which the resulting mixture
was subjected to reaction at room temperature for 3 hours.
To this solution was added 15 ml of water, and the organic
layer was separated, washed with 15 ml of water, and then
dried over anhydrous magnesium sulfate. The solvent was
removed by distillation under reduced pressure, and ~to i~lze
crystalline material thus obtained was added 15 ml of
diethyl ether, after which crystals were collected by
filtration to obtain 660 mg (yield 81.90 of methyl
2- ( 2 , 4-difluorophenylamino) -5-fluoro-6- (2 , 4 , 6-trimetlzyl~°-
benzenesulfonyloxy)nicotinate having a melting point of
153-155°C.
Melting point: 155-156°C (recrystallized i_ranu el~hy:L
acetate)
IR (KBr) cm 1. vC_~ 1700
NMR (CDC13) S values:
2.33 (3H, s) , 2.59 (6H, s) , 3.92 (3Hr s) F
6.32-6.84 (2H, m) , 6.92 (2H, s) ,
7.35-7.94 (1H, m), 8.05 (1H, d, J=9Hz),
10.17 (1H, bs)
- 92 -

1~~~~~~
1 In the same manner as above, the following
compounds were obtained:
o Methyl 2-(2,4-difluorophenylamino)-5-fluoro-6-methane-
sulfonyloxynicotinate
Melting point: 120-121°C (recrystallized from ethyl
acetate)
IR (KBr) cm 1. vC=~ 1690
NMR (CDC13) d values:
3.30 (3H, s), 3.94 (3H, s), 6.60-7.15 (2H, m),
7.73-8.33 (m) 10.00 (1H, bs)
(2H) ,
8.07 (d, J=9Hz)
o Ethyl 2-(2,4-difluorophenylamino)-5-fluoro-6-(2,4,6-
triisopropylbenzenesulfonyloxy)nicoti.nate
Melting point: 147-148°C (recrystallized from ethyl
acetate)
MR (KBr) cm 1. vC=~ 1700
NMR (CDC13) d values:
1.21 (12H, d, J=7Hz), 1.28 (6H, d, J=7Hz),
1.40 (3H, t, J=7Hz), 2.55-3.30 (1H, m),
3.70-4.60 (m) 6.20-7.30 (m)
(4H) , . ~ (4I~:}
4.73 (q, J=7Hz) 7 20 (s)
7.50-8.30 (m) 10.33 (1H, bs)
(2H) ,
8.10 (d, J=9Hz)
Referential Example 7
In 7 ml of N,N-dimethylformamide was suspended
700 mg of methyl 6-chloro-2-(2,4-difluorophenylamino)-5-
- 93 -

13~0~~~~
1 fluoronicotinate, and to the resulting suspension were
added 340 mg of triethylamine and 210 mg of ethanethiol at
room temperature, after which the resulting mixture was
subjected to reaction at 50°C for 4 hours. Subsequently,
40 ml of ethyl acetate and 30 ml of water were added to
the reaction mixture, and the pH of the mixture was adjusted
to 2 with 2 N hydrochloric acid. The organic layer was
separated, washed with successively with 20 ml of water and
20 ml of saturated aqueous sodium chloride solution, and
then dried over anhydrous magnesium sulfate. The solvent
was removed by distillation under reduced pressure, and
to the crystalline material thus obtained was added 10 ml of
hexane, after which crystals were collected by filtration
to obtain 620 mg (yield 81.9°x) of methyl 6-ethylthio-2-
(2,4-difluorophenylamino)-5-fluoronicotinate having a melting
point of 113-114°C.
Melting point: 113.5-114°C (recrystallized from
diisopropyl ether)
IR (KBr) cm 1 vC=0 1680
NMR (CDC13) d values:
1.29 (3H, t, J=7Hz), 3.07 (2H, q, J=7Hz),
3.90 (3H, s), 6.50-7.20 (2H, m),
7.66 (1H, d, J=lOHz), 7.80-8.50 (1H, m),
10.00 (1H, bs)
In the same manner as above, methyl 2-(2,4-
difluorophenylamino)-5-fluoro-6-phenylthionicotinate was
obtained.
- 94 -

L340~4~3
1 blelting point: 128-128.5°C (recrystallized from
diisopropyl ether)
IR (KBr) cm 1. vC=~ 1685
NMR (CDC13) d values:
3.90 (3H, s), 6.0-8.0 (m)
(9H) ,
7.77 (d, J=lOHz)
10.25 (1H, bs)
Referential Example 8
In 10 ml of N,N-dimethylformamide was suspended
1.00 g of methyl 6-chloro-2-(2,4-difluorophenylamino)-5-
fluoronicotinate, and to the resulting suspension were
added 750 mg of 3-aminopyrrolidine dihydrochloride, and
1.44 g of triethylamine, after which the resulting mixture
was subjected to reaction at 70°C for 30 minutes.
Subsequently, to the reaction mixture were added 50 ml of
chloroform and 50 ml of water, and the organic layer was
separated, washed successively with 25 ml of water and
ml of saturated aqueous sodium chloride solution, and
then dried over anhydrous magnesium sulfate. The solvent
20 was removed by distillation under reduced pressure, and
to the crystalline material thus obtained was added 5 ml of
diethyl ether, after which crystals were collected by
filtration to obtain 1.10 g (yield 95.10 of methyl 6--(3-
amino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-
25 fluoronicotinate having a melting point of 139-140°C.
IR (KBr) cm 1. vC-~ 1670
NbiR (CDC13) b values:
- 95 -

~344t~48
1 1.58-2.27 (2H, m), 3.17-4.10 (m)
(8H)
3.84 (s)
6.57-7.12 (2H, m), 7.58 (1H, d, J=l4Hz),
8.10-8.62 (1H, m) , 10.32 (1H, bs)
In the same manner as above, methyl 6-(4-acetyl--
1-piperazinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinate
was obtained.
Melting point: 172-173°C (recrystallized from ethyl
acetate)
IR (KBr) cm 1. vC=0 1680, 1650
NMR (CDC13) d values:
2.13 (3H, s), 3.32-4.12 (m)
(11H) ,
3.85 (s)
6.57-7.07 (2H, m), 7.68 (1H, d, J=l3Hz),
7.77-8.18 (1H, m), 10.05 (1H, bs)
Referential Example 9
In 6.5 ml of chloroform was dissolved 650 mg of
methyl 6-(3-amino-1-pyrrolidinyl)-2-(2,4-difluorophenyl-
amino)-5-fluoronicotinate, and 190 mg of acetic anhydride
was added to the resulting solution, after which the
resulting mixture was subjected to reaction at room tempera-
ture for 10 minutes. The solvent was then removed by
distillation under reduced pressure. To the crystalline
material thus obtained was added 2 ml of diethyl ether,
after which crystals were collected by filtration to obtain
720 mg (yield 99.40 of methyl 6-(3-acetylamino-1-
- 96 -

1 pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicoti-
nate having a melting point of 199-200°C.
Melting point: 202-203°C (recrystallized from ethyl
acetate)
IR (KBr) cm 1. vC=O 1675
NMR (CDC13-DMSO-d6) b values:
1.63-2.27 (m) 3.38-4.62 (m)
(5H) , (8H) ,
1.91 (s) 3.82 (s)
6.63-7.17 (2H, m), 7.62 (1H, d, J=l4Hz),
7.83-8.60 (2H, m), 10.30 (1H, bs)
Referential Example 10
In 3 ml of N,N-dimethylformamide was suspended
120 mg of 3-aminopyrrolidine dihydrochloride, and 250 mg
of triethylamine was added to the resulting suspension,
after which the resulting mixture was subjected to reaction
at room temperature for 5 minutes. Thereafter, 300 mg of
methyl 2-(2,4-difluorophenylamino)-5-fluoro-6-(2,4,6-tri-
methylbenzenesulfonyloxy)nicotinate was added to the
reaction mixture, and the resulting mixture was subjected
to reaction at room temperature for 1.5 hours. To the
reaction mixture were added 10 ml of chloroform and 10 ml
of water, and the organic layer was separated, washed
successively with 10 ml of water and 10 ml of saturated
aqueous sodium chloride solution, and then dried over
anhydrous magnesium sulfate. Subsequently, 100 mg of acetic
anhydride was added to the organic layer, and the resulting
mixture was subjected to reaction at room temperature for

1 10 minutes, after which the solvent was removed by
distillation under reduced pressure. To the crystalline
material thus obtained was added 5 ml of diethyl ether, and
crystals were collected by filtration to obtain 210 mg
(yield 82.40 of methyl 6-(3-acetylamino-1-pyrrolidinyl)-
2-(2,4-difluorophenylamino)-5-fluoronicotinate. The
physical properties of this compound were identical with
those of the compound obtained in Refer.entia~. Example 9.
In the same manner as above, methyl 6-(4-acetyl-
1-piperazinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinate
was obtained.
The physical properties of this compound were
identical with those of the cobtained in Referential I~canple 8.
Referential Example 11
l5 In 39 ml of N,N-dimethylformamide was dissolved
3.89 g of methyl 2-(2,4-difluorophenylarnino)-5-fluoro-6-
(mesitylenesulfonyloxy)nicotinate, and to the resulting
solution were added 1.34 g of thiophenol and 1.23 g of
triethylamine, after which the resulting mixture was
subjected to reaction at room temperature for 5 hours.
Subsequently, 120 ml of ethyl acetate and 120 ml of water
were added to the reaction mixture, and the pH of the mix-
ture was adjusted to 2.0 with 2 N hydrochloric acid. The
organic layer was separated, washed successively with 80 ml
of water and 80 ml of saturated aqueous sodium chloride
solution, and then dried over anhydrous magnesium sulfate.
The solvent was removed by distillation under reduced
- 98 -

i~~o~~g
1 pressure, and to the crystalline material thus obtained was
added 20 ml of n-hexane, after which the crystals thus
deposited were collected by filtration to obtain 2.85 g
(yield 90.20 of methyl 2-(2,4-difluorophenylamino)-5-
fluoro-6-phenylthionicotinate having a melting point of
126-128°C. The physical properties of this compound were
i d a n t i c a 1 w i th t h o s a o f t h a compow~d obtained i n Referential
~cample 7 .
In the same manner as above, methyl 2-(2,4-
difluorophenylamino)-6-ethylthio-5-fluoronicotinate was
obtained. The physical properties of this compound were
identical with those of the ~~ o~'~ined in Referential Example 7.
Referential Example 12
In 30 ml of methanol was suspended 3.00 g of
methyl 2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxy
nicotinate, and 16.1 ml of 2 N aqueous sodium hydroxide
solution was added thereto at room temperature, after ~ehich
the resulting mixture was subjected to reaction under reflux
for 4 hours. Subsequently, the reaction mixture was added
to a mixture of 60 ml of ethyl acetate and 60 ml of water,
and the aqueous layer was separated. The aqueous layer was
adjusted to pH 1.0 with 6 N hydrochloric acid, and the
crystals thus deposited were collected by filtration, washed
successively with 15 ml of water and 15 ml of isopropyl
alcohol to obtain 2.68 g (yield 93.70 of 2-(2,4-difluoro-
phenylamino)-5-fluoro-6-hydroxynicotinic acid having a
melting point of 213-216°C.
_ 99 -

1340~4~
1 Melting point: 215-216°C (recrystallized from acetone-
ethanol (1:1 by volume))
IR (KBr) cm 1. vC=O 1700
NMR (DMSO-d6) d values:
6.65-7.58 (2H, m) , 7.86 (1H, d, J=llHz) ,
8.12-8.68 (1H, m) , 10.49 (lfI, bs)
In the same manner as above, 5-fluoro-2-(4-fluoro-
phenylamino)-6=hydroxynicotinic acid was obtained.
Melting point: 216-217°C (recrystallized from acetone-
methanol (l:l by volume))
IR (KBr) cm 1. vC=O 1685 (sh)
NMR (DMSO-d6) d values:
6.84-7.94 (5H, m) , 10.33 (1H, bs)
Referential Example 13
In 60 ml of tetrahydrofuran was dissolved 2.00 g
of methyl 2-(2,4-difluorophenylamino)-5-fluoro-6-methoxy-
nicotinate, and 25.5 ml of 1 N aqueous sodium hydroxide
solution was added thereto at room temperature, after which
the resulting mixture was subjected to reaction under
reflux for 7 hours. Subsequently, the solvent was removed
by distillation under reduced pressure, and to the residue
thus obtained were added 100 ml of ethyl acetate and 100 ml
of water, after which the pH of the resulting mixture was
adjusted to 2.0 with 2 N hydrochloric acid. The organic
layer was washed successively with 50 ml of water and 50 ml
of saturated aqueous sodium chloride solution, and dried
- loo -

13~U~~~
1 over anhydrous magnesium sulfate. The solvent was removed
by distillation under reduced pressure, and to the crystal-
line material thus obtained was added 10 ml of diethyl
ether, after which crystals were collected by filtration
to obtain 1.40 g (yield 73.3%) of 2-(2,4-difluorophenyl-
amino)-5-fluoro-6-methoxynicotinic acid having a melting
point of 237-240°C.
Melting point: 239-240°C (recrystallized from acetone)
IR (KBr) cm 1. vC-0 1665
NMR (DMSO-d6) d values:
3.98 (3H, s), 6.76-7.48 (2H, m), 7.86 (1H, d,
J=llHz) , 8.10-8.60 (1H, m) , 10.51 (1H, bs)
In the same manner as above, the following
compounds were obtained:
0 6-Chloro-2-(2,4-difluorophenylamino)-5-fluoron.icotinic
acid
Melting point: 226-228°C (recrystallized from benzene)
IR (KBr) cm 1. vC-O 1680
NMR (acetone-d6) 8 values:
6.60-7.41 (2H, m), 7.90-8.50 (m)
(2H) r
8.10 (d, J=9Hz)
10.30 (1H, bs) , 10.64 (1H, bs)
0 2-(2,4-Difluorophenylamino)-5-fluoro-6-(2,4,6-tri-
methylbenzenesulfonyloxy)nicotinic acid
Melting point: 179-180°C (recrystallized from benzene)
IR (KBr) cm 1. vC=O 1665
NNIR (acetone-d6) d values:
- 101 -

1 2.32 (3H, s), 2.55 (6H, s), 6.37-8.52 (m)
7.05 (s) (7H)
8.24 (d, J=9I-iz)
10.37 (1H, bs)
0 2-(2,4-Difluorophenylamino)-5-fluoro-6-(2,4,6-tri-
isopropylbenzenesulfonyloxy)nicotinic acid
Melting point: 163.5-164.5°C (recrystallized from
benzene)
IR (KBr) cm 1 vC-~ 1675
CDC13
NMR ( ) d values:
DMSO-d6
1.22 (12H, d, J=7Hz) , 1.30 (6H, d, J=7Hz) ,
2.55-3.30 (1H, m), 3.70-4.40 (2H, m),
6.20-8.30 (m) 9.66 (1H, bs) ,
7.22 (s) (6H) ,
8.18 (d, J=9Hz)
10.57 (1H, bs)
0 6-Ethylthio-2-(2,4-difluorophenylamino)-5-fluoro-
nicotinic acid
Melting point: 209-210°C (recrystallized from benzene)
IR (KBr) cm 1. vC=O 1665
NMR (acetone-d6) d values:
1.30 (3H, t, J=7Hz), 3.14 (2H, q, J=7Hz),
6.70-7.50 (2H, m), 7.60-8.50 (m)
(2H) r
7.80 (d, J=9I-iz)
9.70 (1H, bs) , 10.27 (1H, bs)
0 2-(2,4-Difluorophenylamino)-5-fluoro-6-phenylthio-
nicotinic acid
- .lob -

1 Melting point: 264-265°C (recrystallized from ethyl
acetate-ethanol (1:1 by volume))
IR (KBr) cm 1. vC=O 1660
NMR (DMSO-d6) 8 values:
6.00-7.73 (8H, m), 7.85 (1H, d, J=lOHz),
10.58 (1H, bs)
Referential Example 14
In a mixture of 30 ml of tetrahydrofruran, 10 ml
of methanol and 4 ml of water was suspended 980 mg of
methyl 6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluoro-
phenylamino)-5-fluoronicotinate, and 5.3 ml of 1 N aqueous
sodium hydroxide solution was added thereto, after which
the resulting mixture was subjected to reaction at 65°C for
3 hours. Subsequently, the reaction mixture was added to
a mixture of 50 ml of ethyl, acetate and 50 ml of water,
and the aqueous layer was separated, after which the pH
thereof was adjusted to 2.0 with 1 N hydrochloric aicd. The
crystals thus deposited were collected by filtration and
washed successively with 2 ml of water and 2 ml of ethanol
to obtain 880 mg (yield 93.00 of 6-(3-acetylamino-1-
pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinic
acid having a melting point of 232-234°C.
Melting point: 233.5-236°C (recrystallized from acetone-
methanol (1:1 by volume))
IR (KBr) cm 1. vC-O 1645 ,
NMR (TFA-dl) d values:
-103 -

1 2.00-2.68 (m) 3.62-5.03 (5H, m),
(5H) ,
2.28 (s)
6.82-7.80 (3H, m), 8.27 (1H, d, J=l3Hz)
In the same manner as above, 6-(4-acetyl-1-
piperazinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinic
acid was obtained.
Melting point: 243-244°C (recrystallized from ethyl
acetate-ethanol (1:1 by volume))
IR (KBr) cm 1. vC=0 1670, 1635(sh)
NMR (TFA-dl) ~ values:
2.48 (3H, s) , 3.47-4.40 (8H, m) ,
6.83-7.82 (3H, m), 8.47 (1H, d, J=l3Hz)
Referential Example 15
In 3.9 ml of methanol was suspended 130 mg of
methyl 6-(4-acetyl-1-piperazinyl)-2-(2,4-difluorophenyl-
amino)-5-fluoronicotinate, and 3.33 ml of 2 N aqueous
sodium hydroxide solution was added thereto, after which
the resulting mixture was subjected to reaction under reflux
for 2 hours. To the reaction mixture was added 2 ml of
water, and the pH thereof was adjusted to 8.5 with 1 N
hydrochloric acid, after which the crystals thus deposited
were collected by filtration and washed with 2 ml of water
to obtain 110 mg (yield 98.2g) of 2-(2,4-difluorophenyl-
amino)-5-fluoro-6-(1-piperazinyl)nicotinic acid having a
melting point of 279-281°C.
- 104 -

~~40b~~
1 LR (KBr) cm 1. vC=~ 1625 (sh)
NMR (TFA-dl) d values:
3.53-4.33 (8H, m), 6.87-7.77 (3H, m),
8.53 (1H, d, J=l3Hz)
In the same manner as above, 6-(3-amino-1-
pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoron.icotinic
acid was obtained. '
Melting point: 249-250°C
IR (KBr) cm 1. vC=~ 1630(sh)
NMR (TFA-dl) d values:
2.47-2.92 (2H, m), 3.72-4.23 (2H, m),
4.23-4.73 (3H, m), 6.95-7.77 (3H, m),
8.36 (1H, d, J=l3Hz)
Referential Example 16
In 150 ml of methylene chloride was suspended
5.00 g of 2-(2,4-difluorophenylamino)-5-fluoro-6-methoxy-
nicotinic acid, and 5.98 g of thionyl chloride and 3 drops
of N,N-dimethylformamide were added thereto, after which
the resulting mixture was subjected to reaction under
reflux for 2 hours. The solvent and the excessive thiony7_
chloride were removed by distillation under reduced pres-
sure, and to the crystalline material thus obtained was
added 10 ml of n-hexane, after which crystals were collected
by filtration to obtain 4.87 g (yield 91.70 of 2-(2,4-
difluorophenylamino)-5-fluoro-6-methoxynicotinoyl chloride
having a melting point of 153-154°C.
- 105 -

~3~0~~
1 Melting point: 154-155°C (recrystallized From methylene
chloride)
IR (KBr) cm 1. vC=~ 1680
NMR (CDC13) S values:
3.98 (3H, s), 6.60-7.10 (2H, m),
7.70-8.30 (m) 9.65 (1H, bs)
(2H) ,
8.06 (d, J=lOHz)
In the same manner as above, the compounds shown
in Table 4 were obtained.
- 106 -

I
b
' O N ' _
x o
m oo ~ M ~n ~ s~
M O
f~ ',C tf1 M 'fir'
'J l0 ~ ' I N ' f
_ O ~ _
cp N lD x
I~ . ' ,'~,' . ~fl x N
W f1 x l~ N Wit' W'
~ ~ r--I II
l0 N '-' h ' ~i'
r~ I N
M 1 ' x 00 ~ ' N iI1
r-I O .-. d' N ~ U7 '(~ ',T,' f~ ~.) ~.
U ~ N o ~ ~ x h M o 0
* x r-I ' x N ' ~' N '
-x * M ~ .--m-I ~ cn ~ rC3
r
I I 1
Q'., ~~ O ' tf7 M O N O Ul
$_,' M ~' ~..) 111 N ,'~ x Wit' N 00 M
~p ~ . . ~
N lD Q1 rl " l0 I~ l~ 07
~-1
O * *
O
~1 O
s~ II
U
rl ~ Wn o
cd as o 0
U
--I r-I
U O x .s~ H 1 U
.-I U Z ~ fs~ P~
.Cl
H ~ 2 '-I
b b
N ~ O
N U N O
~r-1 ~", -r-I
o r-I iC ~-I O
N
M -1~ ..~.,' -4-~ ~ r-1
rl U7 I N !!) -r-I
W I ~'t i~ d' ?~'b ~
tf7 L-1 ri ~-1 ~1
~ U ~ I U 1~ N
M S-I y1' ?-1 O -i-s
r~ v 4-a rl '-' 4-1 O
I
M ~-1
1 W O P-i
M I U~ 1
O -rl ~ri
b
O
O
U
O I
-- 10 7 -

I340~4~
O O
O M
M (~
I x x
O N
x .D .--~-,
II ' N N
h x x
N O O U1
U7 x -~.. ~ ~ .I r.. r-I ..Q
n ~- II ,L2 v II
II ~7 h
17 ~ O x
x x ~ O x
r-1 M ~ '1~ r-1 ~ U7 b
I I ~1'
I~ M O l0 N O M N ~f1
I~ N x x ~' ~ M O lfl Q1
~ ~ N N ~ ~ ~ ~ ~ ~ O
Q1 rl " ~'' I~ I~ Q1 l0 r l~ ~-I
-X
'Lj
>~
O
U ~r1 O
tD ~D
d'
N
1
(~ r--1
H
+~ U
U1 N
'J.t ~ -r-I I
S-1 O ~-I O
U S-1
N 4-1 -~ cLf O
Y-I N +~ ~--I
~ N ~
co ?~ U
~ +.~ x ~ s~
0o cd N 1 U i~ I~
I N _t~ a~ ~ O S-I
to ~rl 1 I~ I-I S-1 O
O~ r-W..) r-i '--' W 4-1
I
- lO8 -

~,~4~~4~
1 Referential Example 17
In 10 ml of methylene chloride was dissolved 500
mg of 2-(2,4-difluorophenylamino)-5-fluoro-6-(mesitylene-
sulfonyloxy)nicotinoyl chloride, and 1 ml of a methylene
chloride solution containing 77 mg of imidazole and 120 mg
of triethylamine was dropped into the resulting solution
at -20°C, after which the resulting mixture was subjected
to reaction at room temperature for 30~minutes. Subsequent-
ly, 5 ml of water was added to the reaction mixture, and
the pH thereof was adjusted to 2.0 with 2 N hydrochloric
acid. The organic layer was separated, washed successively
with 5 ml of water and 5 ml of saturated aqueous sodium
chloride solution, and then dried over anhydrous magnesium
sulfate. The solvent was removed by distillation under
reduced pressure, and to the crystalline material thus
obtained was added 2 ml of diisopropyl ether, after which
crystals were collected by filtration to obtain 485 mg
(yield 91.1 0) of 1- [2- (2, 4-difluorophenylamino) -5-fluoro-
6-(mesitylenesulfonyloxy)nicotinoyl]imidazole having a
melting point of 98-101°C.
Melting point: 103-105°C (recrystallized from
diisopropyl ether-diethyl ether (5:2
by volume))
IR (KBr) cm 1. v~=~ 1670
NMR (CDC13) ~ values:
2.33 (3H, s), 2.60 (6H, s), 6.35-8.15 (9H, m),
9.60 (1H, bs)
- 109 -

1 In the same manner as above, the compounds shown in
Table 5 were obtained.
- 110 -

i3~~~~
ao 0
O N
.. ~
U7 M M o0
N U1 I ill
-i I lD
fi3 ~1 N
x x .D x
r-I f~ rl
~O l0
x
N N N
x ~ ,-I
~n
. a; ~
MI ~ a
-I o h o
U ~ x ~ x , N x
~1 (.'~'.,M M r-I
U C~ -- '-' ~' m ~.
~ ~
I
-k -k M 00 tl7
lb
x N x x O N
~ . N ~
Qi M '-' r-1 '-' l~ Q1
v
W k
z I< -x K
N
N O
rl II
U
1~-15-i
~
N a1 0 0 0
fl,x m Im r7
O ~-' lfl l0 to
rl
I -I .-1 ~--i
y
'n C=., H U
z
a~ I x to
.-I o = U z Q w U
b b
H ~z
N N ~. N
r-I rl r-1
W N r-1 r~l I r~ I
~ Q)
ri rl r-y., r-I
~ >~"'
~,
~ I ~ ~ I
.7-.~ I-1 N ~ N
r-1 r-I
U7 U1 -1~ (Il
O i-.~
O
?~ rtf ?, rti
~ ;a
f~ +~ ~-I
~
U U U ?~ U N
?i
N -w N U ~ O U
.LZ
U ~I ~ rti f-I
N rti
v :~
-- O
M N r-i ,7y r-I
r1 'Jy
rl
~ ~r ,~ c~ ~
-- --
~r r-I r-I .i-I r--I
~ .~
I ,~ I N U I U
O
m1 ~ ~ u1
N o 0 o x o, o
x
t~ ~r 1.-I ~ S~I
Y-I O N
r-I r-I 4-I r-I
4-I ~ 4-I
.~
i
b
>~
O N
r1 I I
O N 1-I
U ~ W
- 111 -

~34~~~~
Referential Example 18
in 2 ml of benzene was suspended 200 mg of ethyl 2-[6-
(3-aCetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-
fluoronicotinoyl]acetate) and f00 mg of N,N-dimethylformamlde
dimethylacetal was added thereto, after which the resulting mix-
ture was sub)ected to reaction under reflux for 7 hours. Subse-
quently) the crystals thus deposited were collected by filtration
and washed with 2 ml of diethyl ether to obtain 180 mg (yield
88.1%) of ethyl 7-(3-acetylamino-1-pyrrolldinyl)-1-(2,4-difluoro-
phenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxy-
late having a melting point of 233-236oC.
Melting point: 234-236oC (recrystalilzed from acetone-methanol
(1:1 by volume))
20
30
- 112 -

~~~~e4~
1 NMR (CDC13) d values
1.33 (3H, t, J=7Hz), 1.76-2.47 (m)
(5H) ,
2.10 (s)
3.13-4.02 (4H, m), 4.02-4.93 (m)
(3H) .
4.32 (q, J=7Hz)
6.78-7.70 (4H, m), 8.10 (1H, d, J=8Hz),
8.31 (1H, s)
In the same manner as above, ethyl 7-(4-acetyl-1-
piperazinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-
oxo-1,8-naphthyridine-3-carboxylate was obtained.
Yield: 84.2
Melting point: 219-220°C (recrystallized from acetone)
Referential Example 19
In 2 ml of benzene was suspended 200 mg of ethyl
2-[2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinoyl]-
acetate, and 87 mg of N,N-dimethylformamide dimethyl-
acetal was added thereto, after which the resulting mixture
was subjected to reaction under reflux for 10 hours. There-
after the crystals thus deposited were collected by
filtration. To the crystals thus obtained were added 0.5 ml
of methanol and 1 ml of water, and the pH thereof was
adjusted to 1.0 with 2 N hydrochloric acid, after which the
crystals thus deposited were collected by filtration to
obtain 80 mg (yield 38.90 of ethyl 1-(2,4-difluorophenyl)-
6-fluoro-1,4-dihydro-7-hydroxy-4-oxo-1,8-naphthyridine-3-
carboxylate having a melting point of 243-248°C.
- 113 -

13~~~4
1 Melting point: 250-252°C (recrystallized from acetone-
methanol (1:1 by volume))
IR (KBr) cm 1. vC=~ 1720
NMR (TFA-dl) d values:
1.51 (3H, t, J=7Hz), 4.70 (2H, q, J=7Hz),
7.00-8.10 (3H, m), 8.30 (1H, d, J=8Hz),
9.11 (1H, s)
In the same manner as above, ethyl 6-fluoro-1-
(4-fluorophneyl)-1,4-dihydro-7-hydroxy-4-oxo-1,8-
naphthyridine-3-carboxylate was obtained.
Melting point: 252-253°C (recrystallized from acetone-
methanol (1:1 by volume))
IR (KBr) cm 1. vC=0 1730(sh), 1700
NMR (TFA-dl) 8 values:
1.50 (3H, t, J=7Hz), 4.64 (2H, q, J=7Hz),
7.15-7.84 (4H, m), 8.20 (1H, d, J=9Hz),
9.02 (1H, s)
deferential Example 20
In 4 ml of benzene was suspended 200 mg of ethyl
2-(2-(2,4-difluorophenylamino)-5-fluoro-6-methoxynicotinoyl]-
acetate, and 71 mg of N,N-dimethylformamide dimethylacetal
was added thereto, after which the resulting mixture was
subjected to reaction under reflux for 9 hours. The solvent
was removed by distillation under reduced pressure, and to
the residue thus obtained was added 2 ml of diethyl ether,
after which the crystals thus deposited were collected by
- 114 -

1 filtration to obtain 130 mg (yield 63.3%) of ethyl 1-(2,4-
difluorophenyl)-6-fluoro-1,4-dihydro-7-methoxy-4-oxo-1,8-
naphthyridine-3-carboxylate having a melting point of
190-192°C.
Melting point: 193-194°C (recrystallized from ethyl
acetate)
IR (KBr) cm 1. vC=~ 1730
NMR (CDC1~) d values:
1.38 (3H, t, J=7Hz) , 3.78 (3H, s) ,
4.39 (2H, q, J=7Hz), 6.82-7.82 (3H, m),
8.22 (1H, d, J=9Hz) , 8.46 (1H, s)
In the same manner as above, the compounds shown
in Table 6 were obtained.
- 17.5 -

1~40b4
V7 N N
~
x
0
x n x oo
.
M r7 M
.~ x ~ l~
N
~ I x
U1 tf1 U~ N a1
v 01
M r~ 00
~
N x d' M l0
~ N , .
.~ ~ ~.. . . Zf
~
~
cp N ~1' N N N
~
Op f~ f~
ri
M II ~' II II II
r-I r7 f7 rJ
V . x ~o
. . ~ ....
V -t-~ ~ .1-i u1
~n b" .
r
x x x ~r, x ~ x
x x
V1 ~', M 10 .-vi_
' v
z
I
In l0 f~ 01 tf1 O
N ~
M d' ~1'M M x ~1
tD
M
r-~ N OO rl cN CO
l0 v
W
O
~-' O
U ~., r-t U
tti
o z~0~--w ~ ~
. ,
....
ri
O O
1
H ~ t.~ .~' o M
~
p., H U r ~
N rd r-I r-1
b )~
O
N O N .-.
-rl
y -I O r-I
, r-i l-1 ri O
O
>T V -1.~ +~ N
r-I
~ o f~ (n 00 U7
.!~ U
-.-t t'~ ~, oo ?)
~--~ U cd
r~ ~-1
.-I I U ~ I U 1~
O ~ ~ O
r-1 '-' rl ~-'
4-a 4-1
I
O
O
p O
V
U N
x.16

l3~pr;4~
1 Referential Example 21
In 3 ml of benzene was dissolved 160 mg of ethyl
2-[2-(2,4-difluorophenylamino)-6-ethylthio-5-fluoro-
nicotinoyl]acetate, and 72 mg of N,N-dimethylformamide
dimethylacetal was added thereto, after which the resulting
mixture was subjected to reaction under reflux for 2.5 hours.
The solvent was removed by distillation under reduced
pressure, and 'the residue thus obtained was purified by a
column chromatography [Wako Silica Gel C-200, eluant:
benzene-ethyl acetate (10:1 by volume)] to obtain 115 mg
(yield 70.10) of ethyl 1-(2,4-difluorophenyl)-7-ethylthio-
6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate
having a melting point of 169.5-171°C.
Melting point: 170-171°C (recrystallized from ethyl
acetate)
IR (KBr) cm 1. vC=~ 1730
NMR (CDC13} d values:
1.08 (3H, t, J=7Hz), 1.38 (3H, t, J=7Hz),
2.79 (2H, q, J=7Hz) , 4.38 (2H, q, J=7Hz) ,
6.88-7.83 (3H, m), 8.10 (1H, d, J=9Hz),
8.48 (1H, s)
In the same manner as above, ethyl 1-(2,4-di-
fluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-7-phenylthio-1,8-
naphthyridine-3-carboxylate was obtained.
Melting point: 218.5-220°C (recrystallized from
acetone-methanol (1:1 by volume))
- 1.17 -

134~J64~
1 IR (KBr) cm 1. vC=C 1730, 1700(sh)
NMR (CDC13) d values:
1.36 (3H, t, J=7Hz) , 4.33 (2H, q, J=7Hz) ,
6.44-7.55 (m) 8.12 (1H, d, J=9Hz),
(8H) .
7.25 (s)
8.33 (1H, s)
Referential Example 22
In 4 ml of toluene was suspended 200 mg of ethyl
2-[2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinoyl]-
acetate, and 200 mg of N,N-dimethylformamide dineopentyl-
acetal was added thereto, after which the resulting mixture
was subjected to reaction at room temperature for 4 hours.
The crystals thus deposited were collected by filtration.,
and to the crystals were added 5 ml of ethanol and 5 ml of
water, after which the pH thereof was adjusted to 1.0 with
2 N hydrochloric acid. Thereafter, the crystals thus
deposited were collected by filtration to obtain 155 mg
(yield 75.40) of ethyl 1-(2,4-difluorophenyl)-6-fluoro-
1,4-dihydro-7-hydroxy-4-oxo-1,8-naphthyridine-3-carboxylate
having a melting point of 244-248°C. The physical properties
of this compound were identical with those of the compound
obtained in Referential Example 19.
In the same manner as above, ethyl 6-fluoro-1-
(4-fluorophenyl)-1,4-dihydro-7-hydroxy-4-oxo-1,8-naphthyri-
dine-3-carboxylate was obtained in a yield of 72.80. The
physical properties of this compound were identical with
those of the compound obtainea in Referential Example 19.
- 17.8 -

1 Referential Example 23
(1) In 6 ml of methylene chloride was dissolved 300 mg
of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-(2,4,6-
trimethylbenzenesulfonyloxy)nicotinoyl]acetate, and 135 mg
of N,N-dimethylformamide dimethylacetal and 115 mg of
acetic anhydride were added thereto, after which the result-
ing mixture was subjected to reaction at room temperature
for 30 minutes: To the reaction mixture were added 0.31 ml
of 2 N hydrochloric acid and 3 ml of ethanol; and the
resulting mixture was subjected to reaction at room tempera-
ture for 1 hour, after which 6 ml of methylene chloride and
6 ml of water were added thereto. The organic layer was
separated, washed with 6 ml of saturated aqueous sodium
chloride solution, and then dried over anhydrous magnesium
sulfate. The solvent was removed by distillation under
reduced pressure, and to the crystalline material thus
obtained was added 2 ml of diisopropyl ether, after which
crystals were collected by filtration to obtain 260 mg
(yield 85.10) of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-
dihydro-4-oxo-7-(2,4,6-trimethylbenzenesulfonyloxy)-1,8-
naphthyridine-3-carboxylate having a melting point of
170-173°C. The physical properties of this compound were
i d a n t i c a 1 w i t h t h o s a o f t h a ~OUrx3 obtained in Ref erential
ale 20.
In the same manner as above, the compounds shown
in Table 7 were obtained.
_ 119

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Q oW .
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OO 61 h Q
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(n
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r-I ~ ,.'>~ N N
rtS ~ . h x x
a n h h
h n n
h h
b x
b
--
U rd I ;~ o
l7 .~J N ,~, ,'T'" M
U ~ r~-l o r1 ~
O ~ ,... ..r M
I
h M 01 O
~ ~ ~ r-~ M M h
Q ~-I r-I r-I N
z
Q Q
O ~ O U
h OU w ~ ~I U
Cdr Pa ~ .L~
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O Z ~ ~ rd r-1 ~ h ~o
Q
E-~ ~ ~n U u7
!~ f~ W
N N
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O r--I ~, r--I ~ r--I
r-I rl O " r-~ r-I I O ~-.
rWd -i~ ~ cd ay ~ r-1 v
tT U U +~ N .--I ~ .L.I
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h >~ ~ f~
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N N N ~Jy
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In rd r-I i~'..
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N . . ~ ~ ~ ~ ~ N
N N 1 ~1 I N N N N ~ N N N
x x ~ x x x x x x x ~
r ~ ~ co ~ c~ ~ c~ ~ a, r~ ~ ~ co
n a n a n n n a n a n
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v b ~ ~ ~ ~ ~ v '~ ~ ~ ~ v b (n
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x x c~ x x x x x x oo x x x x oo x x
M N ~ r-I r-1 M M N N ~ r-I rl M N ~ r-I r-1
.... ~ .r ~. .... ~ ~. ~ .-.
I I I
l0 V' r-I lD tI7 r-I f~ N lD r-1 t~ N lt7 O a0 O O
M M CO M ~Il N M N M 61 tn l0 M M tI1 t11 tn
r1 d' lD ~ O~ r-I r-I M d' l0 N OJ r-i W' l0 ~ CO
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S~ .~ .~ .>~
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I I
O = U~ ~ = Cn = Q
I
0 ~_~_~ O
W
- 1 ?. 2 -

l~~On~3
m h m
N N V' LO
h o~ h 00
N ~ ~.
x N ~ ~
N N N ~ ~7 x N N N N ~ N
N
x x x h x ~ x x x x
x ~ N
h ~ h )~ oo II h o~ w~ h ~ a~
h
II II II II ~7 II II II II II
II
h h ~ h h x h h h h -~ v
h
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Z3' U7
f~
N x r-I Ln rl N
x x x ~ x x M x ~-1 x x x h x x
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l0 M d' rlrl ~-'N ri r-I M N r-1
N
h
I 4 1 I O
h CO CO rl M O M lD O lD Q1 l0~Y'CT N
h Lll
N M 01 N d'tn N lfl !I1 M M 07 N V' Zf M
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h l0 h lD h l0 r~ 4-I
rl r-i r-I r-I r-Ir-IN O 'b
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b s='. b s~ tI~
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N x N x .~.1
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o
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M la S.-I ~r ~-I S-! ('~ ~'LS U7
U .--I U rl O >C
a-I ~-- r-I~- 4.-t ~--I H W
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I N
O -1->
O=W O
N
O I
o=w o z
N
O 1 xz
W M U
..r
123 _

1340048
1 (2) The same procedure as in (1) above was repeated,
except that one of the N,N-di-substituted formamide acetals
shown in Table 8 was substituted for the N,N-dimethyl-
formamide dimethylacetal to obtain the results shown in
Table 8.
Table 8
O , O
F COOEt N,N-di-substituted F COCEt
formamide acetal
R2 N NH F Ac O R2 N N F
2
O O
F F
Compound Physical properties
N,N-di-substituted Yield
R2 formamide acetal ($) of objective
compound
Identical with
Me0- Me NCH~O~ 82.3 those of the compound
2 \ O-~ obtain~l in Referential Exam
ple 20
H Identical with
AcN~1 Same as above 87.6 those of the oompourxl
I N - obtained in Referential
Example 18
Same as O
above Me2N -~ ~ 70.5 Same as above
O
Referential Example 24
(1) To 4 ml of toluene was added 540 mg of (N,N-
dimethylformamide-dimethyl sulfate) complex compound, and
85 mg of sodium methoxide was added thereto at 0°C, after
- 124 -

~34~~48
1 which the resulting mixture was subjected to reaction at
0 to 10°C for 1 hour. Subsequently, 200 mg of ethyl 2-[2-
(2,4-difluorophenylamino)-5-fluoro-6-methoxynicotinoylJ-
acetate was further added to the reaction mixture, and the
resulting mixture was subjected to reaction under reflux for
1.5 hours. The reaction mixture was added to a mixture of
8 ml of ethyl acetate and 8 ml of water, and the organic
layer was separated, washed with 5 ml of saturated aqueous
sodium chloride solution, and then dried over anhydrous
magnesium sulfate. The solvent was removed by distillation
under reduced pressure, and to the crystalline material
thus obtained was added 1 ml of diethyl ether, after which
crystals were collected by filtration to obtain 170 mg
(yield 82.8g) of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1F4--
dihydro-7-methoxy-4-oxo-1,8-naphthyridine-3-carboxylate.
The physical properties of this compound were identical with
those of the compound obtained in Referential example 20.
(2) The same procedure as in (1) above was repeated,
except that (N-formylpyrrolidine-dimethyl sulfate) complex
compound was substituted for the (N,N-dimethylformamide
dimethyl sulfate) complex compound to obtain the r_esult5
shown in Table 9.
- 125 -

~.3~Ob4~
Table 9
O ~ O O
F COOEt CN=CH-OMe-MeS04 F COOEt
R2 ~N~NH F R2 ON~N~ F
NaOMe
F F
Compound Yield Physical properties of
2 the objective compound
R (~)
Identical with those of the
Me0- 90.1 compound obtained in Referential
Example 20
H Identical with those of the
AcN ~ 95 _ 9 compound obtained in ~ferential
- Example ~.8
N
1 Referential Example 25
To 6 ml of methylene chloride was added 335 mg
of (N,N-dimethylformamide-dimethyl sulfate) complex
compound, and 65 mg of sodium methoxide was added thereto
at 0°C, after which the resulting mixture was subjected to
reaction at 0 to 10°C for 1 hour. Subsequently, 300 mg of
ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-(2,4,6-
trimethylbenzenesulfonyloxy)nicotinoyl]acetate and 115 mg
of acetic anhydride were added thereto. The resulting
mixture was subjected to reaction at room temperature for
2 hours, and 0.31 ml of 2 N hydrochloric acid and 3 ml of
ethanol were added to the reaction mixture, after which the
- 126 -

~34~~4~
1 resulting mixture was subjected to reaction at room
temperature for 1.5 hours. The reaction mixture was added
to a mixture of 6 ml of methylene chloride and 6 ml of
water, and the organic layer was separated, washed with
6 ml of saturated aqueous sodium chloride solution, and then
dried over anhydrous magnesium sulfate. The solvent was
removed by distillation under reduced pressure, and to the
crystalline material thus obtained was added 2 ml of
diisopropyl ether, after which crystals were collected by
filtration to obtain 245 mg (yield 80.20) of ethyl
1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-7-(2,4,6-
trimethylbenzenesulfonyloxy)-1,8-naphthyridine-3-carboxyJ_ate.
The physical properties of this compound were identical
with those of the compound obtained in Referential Example 20.
1 5 Referential Example 26
In 4 ml of toluene was suspended 200 mg of ethyl
2-[6-(3-amino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-
5-fluoronicotinoyl~acetate, and 170 mg of N,N-dimethyl-
formamide dimethylacetal was added thereto, after which
the resulting mixture was subjected to reaction under r_e~J_ux
for 7 hours. Subsequently, the solvent was removed by
distillation under reduced pressure, and to the residue
thus obtained was added 1 ml of diethyl ether, after which
crystals were collected by filtration to obtain 195 mg
(yield 84.50) of ethyl 1-(2,4-difluorophenyl)-7-[3-(N,N-
dimethylaminomethyleneimino)-1-pyrrolidinyl]-6-fluoro-J_f4-
dihydro-4-oxo-1,8-naphthyridine-3-carboxylate having a
- 127 -

i~~oo~~
1 melting point of 1.36-138°C. This was recrystallized from
ethanol to obtain crystals having a melting point of
137-139°C.
IR (KBr) cm 1. vC=~ 1730, 1690
NMR (CDC13) d values:
1.38 (3H, t, J=7Hz), 1.65-2.15 (2H, m),
2.85 (6H, s) , 3.10-3.95 (5I-I, m) ,
4.34 (2H, q, J=7Hz), 6.75-7.70 (4H, m),
7.92 (1H, d, J=l3Hz), 8.30 (1H, s)
1 0 Referential Example 27
To 4 ml of toluene was added 245 mg of (N,N-
dimethylformamide-dimethyl sulfate) complex compound, and
66 mg of sodium methoxide was added thereto with ice-cooling
after which the resulting mixture was subjected to reaction
at room temperature for 30 minutes. Subsequently, 200 mg
of ethyl 2-[6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-
difluorophenylamino)-5-fluoronicotinoyl]acetate was added
thereto, and the resulting mixture was subjected to reaction
under reflux for 5 hours. To the reaction mixture were
added 20 ml of chloroform and 20 ml of water, and the
organic layer was separated, washed with 20 ml of saturated
aqueous sodium chloride solution, and then dried over
anhydrous magnesium sulfate. The solvent was removed by
distillation under reduced pressure, and the residue thus
obtained was purified by a column chromatography [Wako
Silica Gel C-200, eluant: chloroform-ethanol (50:1 by
volume)) to obtain 190 mg (yield 84.90) of ethyl 2-[6-
12B -

I34~~4
1 (3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-
5-fluozonicotinoyl]-3-(N,N-dimethylamino)acrylate having a
melting point of 184-186°C.
IR (KBr) cm 1. vC=~ 1680, 1635(sh)
NMR (CDC13) 8 values:
1.15 (3H, t, J=7Hz), 1.75-2.30 (m)
(5H) v
1.93 (s)
2.91 (6H, s), 3.25-4.70 (7H, m), 6.45-7.10
(2H, m) , 7.38 (1H, d, J=l4Hz) , 7.53 (1H, s) ,
8.10-8.65 (1H, m) , 11.62 (1H, bs)
Referential Example 28
In 1 ml of dioxane were dissolved 80 mg of ethyl
2-[2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinoyl]~-
acetate, 46 mg of acetic anhydride and 50 mg of ethyl
ortho-formate, and the resulting solution was subjected to
reaction under reflux for 7 hours, after which the solvent
was removed by distillation under reduced pressure. The
residue thus obtained was dissolved 10 ml of methanol and
5 ml of water., and the pH thereof was adjusted to 8.5 with
a 10~ by weight aqueous sodium carbonate solution. The
resulting mixture was subjected to reaction at room tempera-
ture for 30 minutes, and the pH of the reaction mixture
was adjusted to 2.0 with 2 N hydrochloric acid, after
which 20 ml of ethyl acetate and 10 ml of water were added
. 25 thereto. The organic layer was separated, washed succes-
sively with 15 ml of water and 15 ml of saturated aqueous
sodium chloride solution, and then dried over anhydrous
- 129 -

~~~o~~~s
1 magnesium sulfate. The solvent was removed by distillation.
under reduced pressure, and to the residue thus obtained
was added 1 ml of diethyl ether, after which the crystals
thus deposited were collected by filtration to obtain 43 mg
(yield 52.30 of ethyl 1-(2,4-difluorophenyl)-6-fluoro-
1,4-dihydro-7-hydroxy-4-oxo-1,8-naphthyridine-3-carboxylate.
The physical properties of this compound were identical
with those of the compound obtained in Referential Example 19.
Referential Example 29
In 1 ml of dioxane were dissolved 100 mg of
ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-methoxy-
nicotinoyl]acetate, 55 mg of acetic anhydride and 60 mg
of ethyl ortho-formate, and the resulting solution was
subjected to reaction under reflux for 7 hours. Subsequent-
ly, the reaction mixture was added to a mixture of 3 ml of
ethyl acetate and 3 ml of water, and the organic layer was
separated, washed successively with 3 ml of water and 3 ml
of saturated aqueous sodium chloride solution, and then
dried over anhydrous magnesium sulfate. The solvent was
removed by distillation under reduced pressure, and to 'the
crystalline material thus obtained was added 1 ml of
diethyl ether, after which crystals were collected by
filtration to obtain 45 mg (yield 43.8g) of ethyl 1-(2,4-
difluorophenyl)-6-fluoro-1,4-dihydro-7-methoxy-4-oxo-1,8-
naphthyridine-3-carboxylate. The physical properties of
this compound were identical with those of the compound
Obtained 1ri Referential Example 20.
- 130 -

1 Referential Example 30
(1)' Into 4 ml of N,N-dimethylformamide was dropped
250 mg of phosphorus oxychloride with ice-cooling, and 200
mg of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-
methoxynicotinoyl]acetate was added thereto after stirring
at the same temperature for 10 minutes. The resulting
mixture seas subjected to reaction at 50 to 60°C for 3.5
hours. The reaction mixture was poured into 50 ml of
iced water, and 20 ml of chloroform was added thereto,
after which the organic layer was separated, washed with
ml of water, and then dried over anhydrous magnesium
sulfate. The solvent was removed by distillation under
reduced pressure, and to the residue thus obtained was added
5 ml of diethyl ether, after which crystals were collected
15 by filtration to obtain 150 mg (yield 72.2%) of ethyl
7-chloro-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-
1,8-naphthyridine-3-carboxylate having a melting point of
217-220°C. This was recrystallized from an acetone-methanol
mixture (1:1 by volume) to obtain crystals having a melting
20 point of 219-221°C.
Elementary analysis values for Cl7~;lON2C3C1~3
Calcd. (%): C, 53.35; H, 2.63; N, 7.32
Found (~): C, 53.61; H, 2.47; N, 6.96
(2) The same procedure as in (1) above was repeated
using the starting compounds shown in Table 10 to obtain
the objective compound shown in Table 10 in the yields shown
in Table 10.
- 131 -

1~~Q~~~
Table 10
O
I I p
F CCH2COOEt F COOEt
2!~NH -
R F ~ C1 N N F
F F
Starting compound Yield of objective
R2 compound
- 88.9
MeS03- 96.6
Me
Me Q S03- 84.8
Me
(Et0) PO-
2II 84.6
O
(( V r-O) PO-
76.9
O
EtS02- 76.5
~SOZ- 78.9
1 The physical properties of the objective compound
were identical with those of the compound obtained in (1)
above.
- 132 -

1 (3) The same procedure as in (1) above was .repeated
using,ethyl 2-[2-(4-fluorophenylamino)-5-fluoro-6-hydroxy-
nicotinoyl]acetate to obtain ethyl 7-chloro-1-(4-fluoro-
phenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-
carboxylate in a yield of 74.9%.
Melting point: 230-232°C (recrystallized from acetone)
IR (KBr) cm 1. vC=~ 1730, 1700
NMR (CDC13) d values:
1.38 (3H, t, J=7Hz), 4.34 (2H, q, J=7Hz),
6.90-7.60 (4H, m), 8.37 (1H, d, J=7Hz),
8.53 (1H, s)
Elementary analysis values for C17fI11N2~3C1F2
Calcd. (%): C, 55.98; H, 3.04, N, 7.68
Found (%): C, 56.09; H, 2.92; N, 7.68
(4) The same procedure as in (1) above was repeated,
except that one of the halides shown in Table 11 was
substituted for the phosphorus oxychloride to obtain the
results shown in Table 11.
- 133 -
r
i

?~34~~4~
Table 11
O
O
F CCH2COOEt Halide F COOEt
~O
! -N- 'NH N N
Me0 F DMF C1 F
O O
F F
Halide Amount of objective
(Charged amount) compound obtained
(yield)
Diphosgene 150 mg
(160 mg) (72.2%)
Phosphorus
145 mg
pentachloride
(340 mg) (69.8%)
Phosphorus
125 mg
trichloride
(225 mg) (60.1%)
1 In the respective cases, the physical properties
of the objective compounds obtained were identical with
those of the compound obtained in (1) above.
Referential Example 31
(1) In 2 ml of 1,2-dichloroethane was dissolved 7.30 mg
of N,N-dimethylformamide, and 270 mg of phosphorus oxy-
chloride was dropped thereinto with ice-cooling, after which
the resulting mixture was subjected to reaction at the same
temperature for 10 minutes. Thereafter, 200 mg of ethyl
2-[2-(2,4-difluorophenylamino)-5-fluoro-6-methoxy-
- 134 - -

~~4~b~~
1 nicotinoyl]acetate was added to the reaction mixture, and
the resulting mixture was subjected to reaction under .reflux
for 4.5 hours. The reaction mixture was poured into 30 ml
of water, and 30 ml of chloroform was then added thereto.
The organic layer was thereafter separated, washed succes-
sively with 20 ml of water and 20 ml of saturated aqueous
sodium chloride solution, and then dried over anhydrous
magnesium sulfite. The solvent was removed by distillation
under reduced pressure, and the residue thus obtained was
purified by a column chromatography [Wako Silica Gel C-200,
eluant: benzene-ethyl acetate (10:1 by volume)] to obtain
130 mg (yield 62.60) of ethyl 7-chloro-1-(2,4-difluoro-
phenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-
carboxylate_ The physical properties of this compound oac~:nc~
identical with those of the compound obtained in Referential
Example 30.
(2) The same procedure as in (1) above was repeated,
except that 160 ml of N-formylpyrrolidine was substituted
for the N,N-dimethylformamide to obtain 135 mg (yield 65.Oo)
of ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-
dihydro-4-oxo-1,8-naphthyridine-3-carboxylate. The physical
properties of this compound were identical with those of
the compound obtained in Referentiat_ example 30 (.1) .
Referential Example 32
In 4 ml of ethanol was suspended 200 mg of ethyl 2-
[6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenyl-
amino)-5-fluoronicotinoyl]-3-(N,N-dimethylamino)acrylate, and
- 135 -
S

._. ~3~~~~~
1 0.4 ml of 1 N hydrochloric acid was added thereto, after
which the resulting mixture was subjected to reaction at
room temperature for 5 minutes. Subsequently, to the
reaction mixture were added 10 ml of chloroform and 10 ml
of water, and the organic layer was separated, washed
successively with 10 ml of water and 10 ml of saturated
aqueous sodium chloride solution, and then dried over
anhydrous magnesium sulfate. The solvent was removed by
distillation under reduced pressure, and to the crystalline
material thus obtained was added 4 ml of diethyl ether, after
which crystals were collected by filtration to obtain 180 mg
(yield 98.6%) of ethyl 7-(3-acetylamino-1-pyrrolidinyl)-1-
(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-
naphthyridine-3-carboxylate. The physical properties of this
compound were identical with those of the compound obtained
ii1 Referential Example 18.
Referential Example 33
In 4 ml of 'ethanol was suspended 200 mg of ethyl
2-[6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenyl
amino)-5-fluoronicotinoyl]-3-(N,N-dimethylamino)acrylate,
and 4 ml of 6,N hydrochloric acid was added thereto, after
which the resulting mixture was subjected to reaction under
reflux for 3.5 hours. Subsequently, the solvent was removed
by distillation under reduced pressure, and to the crystal-
line material thus obtained was added 2 ml of ethanol, after
which crystals were collected by filtration to obtain 145 mg
(yield 85.4%) of 7-(3-amino-1-pyrrolidinyl)-1-(2,4-
- 136 -

1340~~g
1 difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-
3-carboxylic acid hydrochloride.
Melting point: 247-250°C (decomp_) (recrystallized from
cone. hydrochloric acid-ethanol (1:3 by
volume))
IR (KBr) cm 1 vC=~ 1730
NMR (TFA-dl) d values:
2.23-2.95 (2H, m), 3.38-4.83 (5H, m),
6.95-7.90 (3H, m), 8.22 (1H, d, J=llHz),
9.18 (1H, s)
Referential Example 34
In 20 ml of N,N-dimethxlformamide was dissolved
1.00 g of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-
7-hydroxy-4-oxo-1,8-naphthyridine-3-carboxylate, and 570 mg
of potassium carbonate and 520 mg of dimethyl sulfate were
added thereto at room temperature, after which the resulting
mixture was subjected to reaction at the same temperature
for 4 hours. To the reaction mixture were added 50 ml of
water and 50 ml of ethyl acetate, and the organic layer was
separated, washed successively with 100 ml of water and
20 ml of saturated aqueous sodium chloride solution, and
then dried over anhydrous magnesium sulfate. The solvent
was removed by distillation under reduced pressure, and -to
the crystalline material thus obtained was added 5 ml of
diethyl ether, after which crystals were collected by
ffiltration to obtain 950 mg (yield 91.50) of ethyl 1-(2,4-
difluorophenyl)-6-fluoro-1,4-dihydro-7-methoxy-a_-oxo-1,8-
- 137 _

~.~~0648
1 naphthyridine-3-carboxylate. The physical properties o.f
this compound were identical with those of the compound
obtained 1.n Referential Example 20.
Referential Example 35
In 30 ml of methylene chloride was suspended
3.00 g of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-
7-hydroxy-4-oxo-1,8-naphthyridine-3-carboxylate, and 1.02
g of triethylamine and 2.20 g of ortho-nitrobenzenesulfonyl
chloride were added thereto with ice-cooling, after which
the resulting mixture was subjected to reaction at the same
temperature for 30 minutes and then at room temperature
for 6 hours. The reaction mixture was washed with three
50-ml portions of water and then dried over anhydrous
magnesium sulfate. The solvent was removed by distillation.
under reduced pressure, and to the residue thus obtained
was added a mixture of 6 ml of ethyl acetate and 12 ml of
diethyl ether, after which the crystals thus despotied
were collected by filtration to obtain 4.40 g (yield 97.20)
of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-7-
(2-nitrobenzenesulfonyloxy)-4-oxo-1,8-naphthyridine-3-
carboxylate having a melting point of 157-160°C.
Melting point: 162-163°C (recrystallized from acetone
n-hexane (10:1 by volume)
IR (KBr) cm 1. vC=O 1730, 1700(sh)
NMR (DrISO-d6) 8 values:
' - 138 -

~.~44~~g
1 1.30 (3H, t, J=7Eiz) , 4.24 (2i3, q, J=7Hz) ,
7.03-8.26 (7Hi, m) , 8.64 (1.H, d, J=9Hz) ,
8.72 (1H, s)
In the same manner as above, the compounds shown
in Table 12 were obtained.
- 139 -

1
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_ 140

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x ~O - x ~ x x x n h x N
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r-I N N N N I r-I
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w w w x
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r--I U1 r-1 U~ U7 ~r! -r-I
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- 7.41 -

-.
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x ,~ I x ~-I m
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- 142 -

ro ro
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143

1340~4~
1 Referential Example 36
In 5 ml of anhydrous acetonitrile was suspended 50U
mg of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-7-
hydroxy-4-oxo-1,8-naphthyridine-3-carboxylate, and 150 mg of
triethylamine and 410 mg of diphenylphosphoryl chloride were
added thereto with ice-cooling, after which the resulting
mixture was subjected to reaction at room temperature for
2 hours. To the reaction mixture were added 25 ml of
methylene chloride and 25 ml of water, and the organic layer
was separated, washed successively with two 20-ml portions
of water and 20 ml of saturated aqueous sodium chloride
solution, and then dried over anhydrous magnesium sulfate.
The solvent was removed by distillation under reduced
pressure, and to the residue thus obtained was added 15 ml
of diethyl ether, after which the crystals thus deposited
were collected to obtain 700 mg (yield 85.50 of ethyl
1-(2,4-difluorophenyl)-7-(diphenoxyphosphinyloxy)-6-
fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate
having a melting point of 144-147°C. The physical properties
of this compound were identical with those of the compound
Obtained i.n Referential 1?xamPle 23.
In the same manner as above, ethyl 7-(diethoxy-
phosphinyloxy)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-
4-oxo-1,8-naphthyridine-3-carboxylate was obtained, and the
physical properties of this compound were identical with
those of the compound obtained in Referential Example 23.
- 144 -

~3~~~~~3
1 Referential Example 37
In 5 ml of pyridine was suspended 500 mg of ethyl
1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-7-hydroxy-4-
oxo-1,8-naphthyridine-3-carboxylate, and 770 mg of
diphenylphosphoryl azide was added thereto, after which the
resulting mixture was subjected to reaction at 80°C for 4
hours. The solvent was thereafter removed by distillation
under reduced pressure, and to the residue thus obtained
were added 10 ml of ethyl acetate and 10 ml of water, after
which the pH of the resulting mixture was adjusted to 2.0
with 6 N hydrochloric acid. The organic layer was then
separated, washed successively with 5 ml of saturated aqueous
sodium hydrogencarbonate solution and 5 ml of water, and
then dried over anhydrous magnesium sulfate. The solvent
was removed by distillation under reduced pressure, and t=o
the residue thus obtained was added 5 ml of diethyl ether,
after which the crystals thus deposited were collected by
filtration to obtain 440 mg (yield 82.30 of ethyl 7-az.ido-
1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-
naphthyridine-3-carboxylate having a melting point of
176-177.5°C. The physical properties of this compound were
i d a n t i c a 1 w i t h t ho s a o f th a ca~Ow~d obtained in Referential
Example 23.
Referential Example 38
In 10 ml of methylene chloride was dissolved :L.00
g of ethyl 1-(2,4-difluorophenyl)-7-ethylthio-6-fluoro-
1,4-dihydro-4-oxo-1,8-naphthyridine-3-ca rboxylate, and
580 mg of m-chloroperbenzoic acid (purity: 80%) was added
- 145 -

~.34~~~~
1 thereto, after which the resulting mixture was subjected to
reaction with ice-cooling for S hours. The precipitates
were removed by filtration, and to the filtrate thus
obtained was added 10 ml of water, after which the pH
thereof was adjusted to 7.5 with saturated aqueous sodium
hydrogencarbonate solution. The organic layer was there-
after separated, washed with 10 m1 of water, and then dried
over anhydrous magnesium sulfate. The'solvent was removed
by distillation under reduced pressure, and the residue thus
obtained was purified by a column chromatography [Wako
Silica Gel C-200, eluant: toluene-ethyl acetate (10:1 by
volume)] to obtain 810 mg (yield 77.9x) of ethyl 1-(2,4-
difluorophenyl)-7-ethylsulfinyl-6-fluoro-1,4-dihydro-4-oxo-
1,8-naphthyridine-3-carboxylate having a melting point of
150-151°C. The physical properties of this compound were
identical with those of the compound obtained in Referential
Example 23.
In the same manner as above, ethyl 7-benzene-
sulfinyl-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-
1,8-naphthyridine-3-carboxylate was obtained, and the
physical properties of this compound were identical with
those of the compound obtained in Referential Example 23.
Referential Example 39
In 15 ml of methylene chloride was dissolved
1.00 g of ethyl 1-(2,4-difluorophenyl)-7-ethylthio-6-
fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate,
and 1.06 g of m-chloroperbenzoic acid (purity: 800) was
- 146 -

1 added thereto, after which the resulting mixture was
subjected to reaction with ice-cooling for 30 minutes, and
then at room temperature for 4 hours. The precipitates
were removed by filtration, and to the filtrate thus
obtained was added 10 ml of water, after which the pH there-
of was adjusted to 7.5 with saturated aqueous sodium
hydrogencarbonate solution. The organic layer was thereafl~er
separated, washed successively with 10~m1 of water and 10
ml of saturated aqueous sodium chloride solution, and then
dried over anhydrous magnesium sulfate. The solvent was
removed by distillation under reduced pressure, and to the
residue thus obtained was added 10 ml of diethyl ether,
after which the crystals thus deposited were collected by
filtration to obtain 940 mg (yield 87.20 of ethyl 1-(2,4-
difluorophenyl)-7-ethylsulfonyl-6-fluoro-1,4-dihydro-4-oxo-
1,8-naphthyridine-3-carboxylate having a melting point of
215-217°C. The physical properties of this compound were
identical with those of the compound obtained in Referential
Example 23.
In the same manner as above, ethyl 7-benzene-
sulfonyl-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-
1,8-naphthyridine-3-carboxylate was obtained, and the
physical properties of this compound were identical with
those of the compound obtained In Ref_erent.ia.l Example 23.
Referential Example 40
In 8.0 ml of dioxane was suspended 800 mg of
ethyl 7-benzenesulfonyl-1-(2,4-difluorophenyl)-6-fluoro-
_ 147

134043
1 1,4-dihydro-4-oxo-1,8-naphthyric'iine 3-carboxylate, and 4.9
ml ofzrr hydrochloric acid was added thereto, after which
the resulting mixture was subjected to reaction under
reflux for 4 hours. The solvent was removed by distillation
under reduced pressure, and the residue thus obtained was
purified by a column chromatography [Wako Silica Gel C-20U,
eluant: benzene-ethyl acetate (10:1 by volume)] to obtain
560 mg (yield 74.30 of 7-benzenesulforiyl-1-(2,4-difluoro-
phenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-
carboxylic acid having a melting point of 252-258°C.
Melting point: 259-263°C (recrystallized from dioxane)
IR (KBr) cm 1. vC=O 1730
NMR (DMSO-d6) d values:
7.05-7.85 (8H, m), 8.85 (1H, d, J=9Hz),
8.98 (1H, s)
Referential Example 41
In 2.5 ml of phosphorus oxychloride was suspended
500 mg of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-
7-methoxy-4-oxo-1,8-naphthyridine-3-carboxylate, and the
resulting suspension was subjected to reaction under reflex
for 1.5 hours. Subsequently, the solvent was removed by
distillation under reduced pressure, and the crystalline
material thus obtained was washed with 10 ml of diethyl
ether to obtain 430 mg (yield 85.00 of ethyl 7-chloro-7_-
(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-
naphthyridine-3-carboxylate having a melting point of
216-219°C. The physical properties of this compound were
- 14 t3 -

13~4~D~4~
1 i d a n t i c a 1 w i th t h o s a o f t h a c~zrq~u~d obt~-~inoW n
Referential EKaa~le 3o.
Referential Example 42
In 10 ml of conc. hydrochloric acid was suspended
500 mg of ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-
1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, and the
resulting suspension was subjected to reaction under
reflux for 1 hour. The reaction mixture was diluted w.itli
ml of water, and the crystals thus deposited were
collected by filtration, and then washed with 2 ml of water
10 to obtain 450 mg (yield 97.1$) of 7-chloro-1-(2,4-difluoro-
phenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-
carboxylic acid having a melting point of 238-242°C.
Melting point: 242.5-243.5°C (recrystallized from
chloroform-ethanol (2:1 by volume))
Referential. Example 43
In 5 ml of ethanol was suspended 150 mg of 3-
aminopyrrolidine dihydrochloride, and 310 mg of triethy7_-
amine was added thereto to form a solution. Subsequently,
500 mg of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-
dihydro-4-oxo-7-(2,4,6-triisopropylbenzenesulfonyloxy)-
1,8-naphthyridine-3-carboxylate was added thereto, and th.e
resulting mixture was subjected to reaction at room
temperature for 2 hours. Subsequently, 6 ml of water was
added to the reaction mixture, and the crystals thus
deposited were collected by filtration, and washed with
5 ml of water to obtain 330 mg (yield 96.3%) of ethyl
- 149 -

1~40~=~~
1 7-(3-amino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-
fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate
having a melting point of 200-202°C.
Melting point: 206-209°C (recrystallized from ethyl
acetate-ethanol (1:1 by volume))
NMR (TFA-dl) d values:
1.48 (3H, t, J=7Fiz) , 2.19-2.86 (2H, m) ,
3.33-4.90 (7H, m), 6.89-7.85~(3H, m),
8.18 (1F3, d, J=llHz) , 9.04 (1H, s)
In the same manner as above, the compounds shown
in Table 13 were obtained.
- 150 -

.~~~0~~
Table 13
O O
F COOEt F COOEt
R2 O~N~ X ~ N O~N X
O O
NH2
F F
Starting compound Physical properties of Yield
objective compound
X R2
C1
O Identical with the above
F S03- physical properties 90.2
Cl
C1
F C1 O S03- Same as above 92.8
C1
F Me-( Q }-S03- Same as above 55. 5
~--~Me
F Me O S03- Same as above 91e0
Me
Melting point: 192-194°C
NMR (TFA-dl) d values:
i-Pr 1.49 (3H, t, J=7Hz), 2.13-
H i-Pr Q S03- 3.13 (2H, m), 3.23-4.93 95.9
i-Pr (7H, m), 7.03-7.73 (4H,
m) , 8.18 (1H, d, J=l2Hz) ,
9.06 (1H, s)
- 151 _

~3~4~48
1 Referential Example 44
In 4 ml of methylene chloride was dissolved 270 mg
of anhydrous piperazine, and 400 mg of ethyl 1-(2,4-di-
fluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-7-(2,4,6-tri-
isopropylbenzenesulfonyloxy)-1,8-naphthyridine-3-carboxy-
late was added to the resulting solution, after which the
resulting mixture was subjected to reaction with ice-cooling
for 1 hour. To the reaction mixture were added 20 ml of
ethyl acetate and 10 ml of water, and the organic layer was
separated, washed successively with 10 ml of saturated
aqueous sodium hydrogencarbonate solution and 10 ml of
saturated aqueous sodium chloride solution, and then dried
over anhydrous magnesium sulfate. The solvent was remover
by distillation under reduced pressure, and to the crystla-
line material thus obtained was added 5 ml of diethyl
ether, after which crystals were collected by filtration
to obtain 250 mg (yield 91.24) of ethyl 1-(2,4-difluoro-
phenyl)-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-
naphthyridine-3-carboxylate having a melting point of
208-211°C.
Melting point: 220-223°C (recrystallized from acetone-
methanol (l:l by volume))
NMR (TFA-dl) d values:
1.50 (3H, t, J=7Hz), 3.39-3.93 (4H, m),
3.93-4.44 (4H, m) , 4.66 (2H, q, J=7Hz) ,
6.89-7.82 (3H, m), 8.32 (1H, d, J=l2Hz),
9.14 (1H, s)
- 152 -

1340~4~
1 In the same manner as above, the results shown in
Table 19 were obtained.
Table 14
O O
F COOEt F COOEt
R2 O~N~ X ~ H N O~N X
0
F F
Starting Physical properties of Yield
compound
tive
om
nd
o
bj
X R2 p (g)
c
u
o
ec
Melting point: 215-217C
NMR (TFA-dl) d values:
N02 1.51 (3H, t, J=7Hz),
H ~ S03- 3.40-3.88 (4H, m), 4.06- 90..1
4.46 (4H, m), 4.70 (2H,
q, J=7Hz), 7.16-7.78
(4H, m), 8.38 (1H, d,
J=l2Hz), 9.21 (1H, s)
i-Pr
H i-Pr p S03- Same as above 91.1
i-Pr
- Identical with the physical 64
7
F MeSO properties in ReFereotial .
3 ~.xample 44
Me
F jCHS03- Same as above 70.6
Me
F F3CS03- ' Same as above 63.1
- cont'd -
- 153 -

..
Table 14 (cont'd)
F Cl-- p~-S03- Same as above 42.7
F 02N-O- S03- Same as above 47.0
N02
F Od-503- Same as above . 90.5
S03-
F ~ ~ Same as above 66.7
1 Referential Example 45
(1) In 2 ml of. ethanol was suspended 64 mg of 3-
aminopyrrolidine dihydrochloride, and 130 mg of triethyl-
amine was added to the resulting suspension to form a
solution. Subsequently, 200 mg of ethyl 1-(2,4-difluoro-
phenyl)-7-diphenoxyphosphinyloxy-6-fluoro-1,4-dihydro-4-
oxo-1,8-naphthyridine-3-carboxylate was added to the solu~-
tion, and the resulting mixture was subjected to reaction
at room temperature of 1 hour. Subsequently, 3 ml of water
was added to the reaction mixture, and the crystals thus
deposited were collected and washed with 3 ml of water to
obtain 110 mg (yield 75.90 of ethyl 7-(3-amino-1-
pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-
4-oxo-1,8-naphthyridine-3-carboxylate. The physical
- 154 -

~.340~48
properties of this compound were identical with those of
the compound obtained in Referential Example 43.
(2) The same procedure as in (1) above was repeated,
except that 170 mg of ethyl 7-diethoxyphosphinyloxy-1-(2,4-
difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-
naphthyridine-3-carboxylate was substituted for the ethyl
1-(2,4-difluorophenyl)-7-diphenoxyphosphinyloxy-6-fluoro-
1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate to obtain
105 mg (yield 71.5%) of ethyl 7-(3-amino-1-pyrrolidinyl)-1-
(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-
naphthyridine-3-carboxylate. The physical properties of
this compound were identical with those of the compound
obtained in Referential Example 43.
Referential Example 46
In a mixture of 4.5 ml of ethanol and 4.5 ml of
N,N-dimethylformamide was dissolved 400 mg of anhydrous
piperazine, and 450 mg of ethyl 7-azido-1-(2,4-difluoro-
phenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-
carboxylate was added to the resulting solution, after
which the resulting mixture was subjected to reaction at
80°C for 1 hour. The solvent was removed by distillation
under reduced pressure, and to the residue thus obtained
were added 30 ml of ethyl acetate and 30 ml of water, after
which the pH thereof was adjusted to 1.0 with 2 N
hydrochloric acid. The aqueous layer was separated, and 15
ml of chloroform was added to the aqueous layer, after
which the pH thereof was adjusted to 8.5 with 1 N aqueous
sodium hydroxide
- 155 -

y
1 solution. The organic layer was separated, washed succes-
sively with 10 ml of water and 10 ml of saturated aqueous
sodium chloride solution, and then dried over anhydrous
magnesium sulfate. The solvent was removed by distillation
under reduced pressure, and to the residue thus obtained
was added 5 ml of diethyl ether, after which the crystals
thus deposited were collected by filtration to obtain 420
mg (yield 84.00 of ethyl 1-(2,4-difluorophenyl)-6-
fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyri-
dine-3-carboxylate. The physical properties of this
compound were identical with those of the compound obtained
1n Referential Example 44.
Referential Example 47
In 12 ml of N,N-dimethylformamide were suspended
400 mg of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-
dihydro-4-oxo-7-phenylthio-1,8-naphthyridine-3-carboxylate
and 380 mg of anhydrous piperazine, and the resulting
suspension was subjected to reaction at 95 to 100°C for
6 hours. Subsequently, the solvent was removed by distil-
lation under reduced pressure, and to the residue thus
obtained were added 10 ml of ethyl acetate and 30 ml of
water, after which the pH thereof was adjusted to 0.5 with
6 N hydrochloric acid. The aqueous layer was separated and
ml of ethyl acetate was added thereto, after which the
25 pH thereof was adjusted to 9.0 with a 10~ by weight
aqueous potassium carbonate solution. The organic layer
was separated, and the aqueous layer was extracted with two
- 156 -

1~~~648
1 20-ml portions of ethyl acetate, after which the extracts
were combined with the organic layer. The combined layer
was washed with 20 ml of saturated aqueous sodium chloride
solution, and then dried over anhydrous magnesium sulfate.
The solvent was removed by distillation under reduced
pressure, and to the crystalline material thus obtained
was added 5 ml of diethyl ether, after which crystals were
collected by filtration to obtain 230 ring (yield 60.70) of
ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-
7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylate. The
physical properties of this compound were identical with
those of the compound obtained in Referential Example 44.
Referential Example 48
(1) In 3 ml of ethanol was suspended 120 mg of 3-
aminopyrrolidine dihydrochloride, and 250 mg of triethy)_--
amine was added thereto, after which 300 mg of ethyl
7-benzenesulfinyl-1-(2,4-difluorophenyl)-6-fluoro-1,4-
dihydro-4-oxo-1,8-naphthyridine-3-carboxylate was added
thereto. The resulting mixture was subjected to reaction
at room temperature for 3 hours, and to the reaction mixture
was added 10 ml of diethyl ether, after which crystals were
collected by filtration, and washed with 12 ml of water to
obtain 230 mg (yield 83.8%) of ethyl 7-(3-amino-1-
pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-
4-oxo-1,8-naphthyridine-3-carboxylate. The physical
properties of this compound were identical with those of the
compound obtained in Referential Example 43.
- 157 -

~~~~b~~
1 (2) The same procedure as in (1) above was repeated,
except that 270 mg of ethyl 1-(2,4-difluorophenyl)-7-ethyl-
sulfinyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-
carboxylate was substituted for the ethyl 7-benzenesulfinyl-
1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-
naphthyridine-3-carboxylate to obtain 230 mg (yield 83.60 of
ethyl 7-(3-amino-1-pyrorridinyl)-1-(2,4-difluorophenyl)-6-
fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate.
The physical properties of this compound were identical with
those of the compound obtained in Referential Example 43.
Referential Example 49
(1) In 3 ml of ethanol was suspended 120 mg of 3-
aminopyrrolidine dihydrochloride, and 250 mg of triethyl-
amine was added thereto to form a solution. Subsequently,:
300 mg of ethyl 7-benzenesulfonyl-1-(2,4-difluorophenyl)-
6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate
was added to the solution, and the resulting mixture was
subjected to reaction at 45 to 50°C for 4 hours. To the
reaction mixture was added 10 ml of diethyl ether, and
crystals were collected by filtration and washed with 17 A111
of water to obtain 230 mg (yield 86.6$) of ethyl 7-(3-
amino=1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-
dihydro-4-oxo-1,8-naphthyridine-3-carboxylate. The physical
properties of this compound were identical with those o:f
the compound obtained in Referential Example 43.
(2) The same procedure as in (1) above was repeated,
except that 270 mg of ethyl 1-(2,4-difluorophenyl)-7-ethyl
- 158 -

v 1~4~~~'~
1 sulfonyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naph thyridine-3-car-
boxylate was substituted for the ethyl 7-benzenesulfonyl.-1-
(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,B-
naphthyridine-3-carboxylate to obtain 225 mg (yield 84.9$)
of ethyl 7-(3-amino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-
6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate.
The physical properties of this compound were identical
with those of the compound obtained in' Referential Example 43.
Referential Example 50
In 2 ml of methylene chloride was suspended 70 mg
of N-acetylpiperazine monohydrochloride, and 80 mg of tri-
ethylamine was added thereto to form a solution. Sub-
sequently, 200 mg of ethyl 1-(2,4-difluorophenyl)-6-fluoro-
1,4-dihydro-4-oxo-7-(2,4,6-triisopropylbenzenesulfonyloxy)-
1,8-naphthyridine-3-carboxylate was added thereto, and the
resulting mixture was subjected to reaction at room
temperature for 2 hours. To the reaction mixture were
added 8 ml of methylene chloride and 10 ml of water, and.
the organic layer was separated, washed successively with
10 ml of water and 10 ml of saturated aqueous sodium
chloride solution, and then dried over anhydrous magnesi.7.am
sulfate. The solvent was removed by distillation under
reduced pressure, and to the residue thus obtained was
added 5 ml of diethyl ether, after which the crystals thus
deposited were collected by filtration to obtain 140 mg
(yield 93.10 of ethyl 7-(4-acetyl-1-piperazinyl)-1-(2,4-
difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-
- 159 -

.~~4~~4~
1 naphthyridine-3-carboxylate having a melting point of 217-
219°C. The physical properties of this compound were
i d a n t i c a 1 w i t h t h o s a o f t h a d obtained W Referential Example
18.
Referential Example 51
In 6 ml of 6 N hydrochloric acid was suspended
1.00 g of ethyl 7-(3-amino-1-pyrrolidinyl)-1-(2,4-difluoro-
phenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-
carboxylate, and the resulting suspension was subjected to
reaction under reflux for 2 hours. Subsequently, 6 ml of
water was added thereto and crystals were collected by
filtration, and then washed with 2 ml of water to obtain
920 mg (yield 90.20 of 7-(3-amino-1-pyrrolidinyl)-1-(2,4-
difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-
3-carboxylic acid hydrochloride having a melting point of
247-250°C (decomp.). The physical properties of this
compound were identical with those of the compound obtained
i.n Referential Example 33.
In the same manner as above, 7-(3-amino-1-
pyrrolidinyl)-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-
oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride was
obtained.
Melting point: 210-217°C (decomp.)
NMR (TFA-dl) 8 values:
2.20-2.85 (2H, m), 3.48-4.98 (5H, m),
7.07-7.78 (4H, m), 8.18 (1H, d, J=llHz),
9.18 (1H, s)
- 160 -

13404
1 Referential Example 52
In 1.2 ml of 6 N hydrochloric acid was suspended
200 mg of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-
4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylate,
and the resulting suspension was subjected to reaction
under reflux for 2 hours. Subsequently, 2 ml of water was
added thereto and crystals were collected by filtration and
washed with 1 ml of water to obtain 190 mg (yi.e7.d 93.20
of 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-7-(1-
piperazinyl)-1,8-naphthyridine-3-carboxylic acid hydro-
chloride having a melting point of 249-252°C (decomp.).
g p p.) (recrystallized
Meltin oint: 249-252°C (decom
from conc. hydrochloric acid-methanol
(1:2 by volume))
NMR (TFA-dl) d values:
3.33-3.92 (4H, m), 3.92-4.50 (4H, m),
6.90-7.90 (3H, m), 8.30 (1H, d, J=l2Hz),
9.18 (1H, s)
Referential Example 53
In 1 ml of 6 N hydrochloric acid was suspended
100 mg of ethyl 1-(2,4-difluorophenyl)-7-
[3-(N,N-dimethylaminomethyleneimino)-1-pyrrolidinyl]-6-
fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate,
and the resulting suspension was subjected to reaction under
reflux for 2 hours. Subsequently, the solvent was removed
by distillation under reduced pressure, and to the crystal-
line material thus obtained was added 1 ml of ethanol,
_ 161 -

~34~~4g
after which crystals were collected by filtration to obtain
85 mg (yield 94.0%) of 7-(3-amino-1-pyrrolidinyl)-1-(2,4-
difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-
naphthyridine-3-carboxylic acid hydrochloride. The
physical properties of this compound were identical with
those of the compound obtained in Referential Example 33.
Referential Example 54
In 5 ml of 6 N hydrochloric acid was dissolved 500 mg
of ethyl 7-(3-acetylamino-1-pyrrolidinyl)-1-(2,4-
difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-
naphthyridine-3-carboxylate, and the resulting solution was
subjected to reaction under reflux for 4 hours.
Subsequently, the crystals thus deposited were collected by
filtration and washed with 1 ml of water to obtain 390 mg
(yield 84.0%) of 7-(3-amino-1-pyrrolidinyl)-1-(2,4-
difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-
naphthyridine-3-carboxylic acid hydrochloride having a
melting point of 247-250°C (decomp.). The physical
properties of this compound were identical with those of
the compound obtained in Referential Example 33.
Referential Example 55
In the same manner as in Referential Example 54,
except that the reaction time was altered to 2 hours, 1-
(2,4-difluorophenyl)-6-fluoro-7-(1-piperazinyl)-1,4-
dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid
hydrochloride was obtained in a yield of 91.5%. The
physical properties of this compound were identical with
those of the compound obtained in Referential Example 52.
- 162 -