CA1340648C - Process for producing 1-substituted aryl-1, 4-dihydro-4-oxonaphthyridine derivative, intermediates therefor and porcesses for producing the intermediates - Google Patents

Abstract

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.

Description

1 ~44ti43 Thls Invention relates to a novel 2-(5-fluoronicoti-noy)acetic acid derivative of the formula CI):

COOf~a R N NH
X

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;

~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-~~~Ob~3 dihydro-4-oxonaphthyrldine derivative of the formula (~Tj or a salt thereof:
O

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) 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.

° x o x U
O = U z -- m z Gc.~ N
f~
G
O
N ~
U
~ a) Q) ~1-~
;>C
~rI 41 .~ o x .~ 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.

_ g _ 1340b~~8 I
_ ___ __ _____~__ _ _ __ _____ 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~

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 lT o ~.340~~~

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 O
O U
- l~ -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 x x rx 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-.

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 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 ' rd O O _ O
- 1.2 ~3~0~~~3 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 o z ~ ~. ~. ~ o z w ~-' ~ ~ w Oz H
Oz H
w ~ ~ w N x, O O

X~ J

13~~~~8 U

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 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;

.~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.

' ~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, 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.

:~3~0~~3 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.

~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-~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.

(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:

j34~~~8 Reactive derivative in the carboxyl group of F COOH

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

F
( I ) orasalt thereof 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, ~,;~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.

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 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 ~.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.

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:

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.

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.

~~~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, 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 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, :~~~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-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, 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 _. :~~~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 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 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.

(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) 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):

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-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.

~~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 .~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 ~.34~b~8 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 _ 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 ~~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 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 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 ~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.

:~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, 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 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.

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.

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. . r~j ,.~ . -~O N N ~ N O
x x x x o, x h h rl ~ h .
M n n -- n M .
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r-I ~r' ~.
U -t.~ ~' ~ .r .t-y o~ -h I I
o t7 0 ~, '~.C~-n .'T'r ~ L(1 ..fir ~r' M
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r~ ~ r-~ ~'., r-I O r-i N
tr U rt cmn r~ N
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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~ (''~
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M M
N I~ I~
r~ r~
r-1 H -b rd N O Q., N N O
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r~i I N r--1 S~
r-I O .~ ~-t O
tf1 (CS U7 ~-1 M (d UJ
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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
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vn o o u1 o N M V' M I~
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N x ~ N _. N >~ ~
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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 ~---z I
I
z C z' x z U U

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 ~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)-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 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)-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 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 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 ~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 ~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 .

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 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 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 ~.~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 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:

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:

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 ~.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 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) .-_ ~ - ~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), ;.
:_ ~:

~.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 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:

~<
.,, ~~~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

F
Compound Yield Z ( o) MeS03- 41.7 O

(~O) 2P0- 50. 7 ~

O

CO- 4 4 . 4 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 .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 ' .
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) 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)-5-13~0~~~~
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.

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:

~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-1-1 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 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:

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 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:

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.

~~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.

~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.

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 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

I340~4~
O O
O M
M (~
I x x O N
x .D .--~-, II ' N N
h x x 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

(~ r--1 H
+~ U

'J.t ~ -r-I I
S-1 O ~-I O

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

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

U ~ W

~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)) ~~~~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.

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 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 ~

x 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

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 ., ~~~Ob'~~
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-i N ~f1 ~O
Q oW .
~rl ~-' tf7 N h OO 61 h Q
U
I
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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~
O O
O Z ~ ~ rd r-1 ~ h ~o Q
E-~ ~ ~n U u7 !~ f~ W
N N
-~, ~ r-I N I r-I N
~r-I 3 -r-i ~ ~ W r-I
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
. ri ~ cn U O ~ oo tn -~-~ N
.1-) N ~n rd ~ r-1 t~ ~-, N +~ N r-I
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CO C'rl r--I lf7 5~, t~ a~ c~ co O

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N

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,p .CZ .L7 I I N O O O I

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r O O O

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r ~ ~ co ~ c~ ~ c~ ~ a, r~ ~ ~ co n a n a n n n a n a n h h h ~ ~ h h h h h h x x x OJ M
v b ~ ~ ~ ~ ~ v '~ ~ ~ ~ v b (n tI1 N ~D
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
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b S~ .~ .~ .>~

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r-1 O '"' ~ ~ rl .1-~ O rl O r-I
O r ~
N r-I .~., r~ .1-~ .~-. I ~ N
l~ !n U O ~ N tn -I, O ?i M U1 U r-I ~-.
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O = U~ ~ = Cn = Q
I
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h o~ h 00 N ~ ~.

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N

x x x h x ~ x x x x x ~ N

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h II II II II ~7 II II II II II
II

h h ~ h h x h h h h -~ v h x M x >~

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N x r-I Ln rl N

x x x ~ x x M x ~-1 x x x h x x x x l0 M d' rlrl ~-'N ri r-I M N r-1 N

h 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
M h ~ . . . . . . . . . ~ r.l .-I ~-I o 0om * ~r ~0 00 r-I~r~ co m ~ U
M m 0o O ~7 C~ U

b , _ . ~ M O O

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s~ ~ .~ .s~ ~ +~

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b s='. b s~ tI~
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..r 123 _ 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

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 ~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.

~.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 ~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 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-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 ~~~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.

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.

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.

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.

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-~~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 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-(2,4-1340~~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.

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U ~ 01 Wo N O c'J X ~-i rd x ~ x u1 S-r S-a U N O
H W H W r-I v 4--I rd .-f~. 'J
G4 C~-~ f~, I
1.-1 M
I W O W

O -r-I -ri M
O
W
N I
,"'L, ~ rl 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.

~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 ~.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 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 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 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.

.~~~0~~
Table 13 O O
F COOEt F COOEt R2 O~N~ X ~ N O~N X
O O

F F
Starting compound Physical properties of Yield objective compound O Identical with the above F S03- physical properties 90.2 Cl F C1 O S03- Same as above 92.8 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) 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

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 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 -..
Table 14 (cont'd) F Cl-- p~-S03- Same as above 42.7 F 02N-O- S03- Same as above 47.0 F Od-503- Same as above . 90.5 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 ~.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 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 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.

~~~~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$) of ethyl 7-(3-amino=1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate. The physical properties of this compound were identical with those o:f the compound obtained in Referential Example 43.
(2) The same procedure as in (1) above was repeated, except that 270 mg of ethyl 1-(2,4-difluorophenyl)-7-ethyl v 1~4~~~'~
1 sulfonyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naph thyridine-3-car-boxylate was substituted for the ethyl 7-benzenesulfonyl.-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,B-naphthyridine-3-carboxylate to obtain 225 mg (yield 84.9$) 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-.~~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) 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.

Claims (8)

1. A 2-(5-fluoronicotinoyl)acetic acid derivative of the general formula:
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.

5. A process for producing a 2-(5-fluoro-nicotinoyl)acetic acid derivative of the general formula:
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:
wherein R2 and X are as defined above, with a compound of the general formula:
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 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.