FI85703C - FOERFARANDE FOER FRAMSTAELLNING AV 1,4 -DIHYDRO-4-OXONAFTYRIDINDERIVAT. - Google Patents

Description

χ ε 5 7 03

A process for preparing a 1,4-dihydro-4-oxo-naphthyridine derivative

This invention relates to a process for the preparation of a 1,4-dihydro-4-oxonaphthyridine derivative of the formula i, o 10 F J1 COOR1

ΊΓοΊΓ J

- ‘Φ’

F

wherein R1 is a hydrogen atom or a carboxyl protecting group conventional in pyridonecarboxylic acid chemistry, X is a hydrogen atom or a fluorine atom and Y is a halogen atom, or a salt thereof.

In Program and Abstracts of the 24th ICAAC, p. 102-104 and Japanese Patent Application Kokai (not studied) JP 228 479/85 discloses that 1-substituted aryl-1,4-dihydro-4-oxonaphthyridine derivatives of formula III

r2s I x (ui)

F

35 r ΰ 7 n 7 2 'w. u Ο wherein R1 and X have the same meaning as above and R2a is a 3-amino-1-pyrrolidinyl group whose amino group can be protected or a 1-piperazinyl group whose imino group can be protected and their salts have a strong antibacterial effect on gram-positive and gram-positive negative bacteria. When given orally or parenterally, their blood levels become high. In addition, they have excellent properties, such as very good operational safety.

Finnish patent publications 66,379, 77,862 and 80,453 describe processes for the preparation of 1,4-dihydro-1,8-naphthyridine derivatives. However, these known methods are different from the method according to the invention.

The present invention relates to a completely new process for the preparation of 1,4-dihydro-4-oxo-1,8-naphthyridine derivatives. This new process is a one-step process that readily obtains a 1,8-naphthyridine ring from 2- (5-fluoronicotinyl) acetic acid-20 Posta used as a starting material while simultaneously halogenating the 7-position of the ring.

FI patent 66,379 discloses a different process for the preparation of 1,4-dihydro-4-oxo-1,8-naphthyridine derivatives.

FI patent 77,862, on the other hand, describes a process for the preparation of both 1,2,3,4-tetrahydro-4-oxo-1,8-naphthyridine and 1,4-dihydro-4-oxo-1,8-naphthyridine.

FI patents 66,379 and 77,862 relate to methods in which only ring formation occurs. In contrast, in the process of the present invention, both ring formation and 7-position halogenation occur in one and the same step. In the past, ring formation and halogenation have had to be performed in separate steps.

Compounds of formula I and their salts are useful intermediates in the preparation of compounds of general formula III.

3 - ^

The novel process according to the invention for the preparation of 1,4-dihydro-4-oxonaphthyridine derivatives of the formula I and their salts is characterized in that a compound of the formula II is administered.

F. C CH_COOR

.., ¾¾.

F

Wherein R11 is a carboxyl protecting group conventional in pyridonecarboxylic acid chemistry; R 2b is a hydroxyl group or an optionally substituted C 1-12 alkoxy, C 1-5 alkanesulfonyloxy, benzenesulfonyloxy, C 1-4 alkanesulfonyloxy, benzenesulfonyloxy, di-C 1-4 alkoxyphosphinyloxy or diphenoxyphosphinyloxy group; and X is as defined above;

or a salt thereof to react with a Vilsmeier reagent derived from a Ν, Ν-disubstituted formamide having. 25 formula III

R3. Wherein R 3 and R 4 may be the same or different and are C 1-6 alkyl or together with the nitrogen atom to which they are attached may form a nitrogen-containing heterocyclic group, and phosphoryl halide or carbonyl halide, and c 7 n 7 4 υ; / υ j if necessary, remove the carboxyl protecting group or convert the product to a salt.

The process of the invention can be illustrated in Reaction Scheme 1.

5 Reaction Scheme 1

Vilsmeier reagent, q 'derived

Il i F c-cn rnnn α 's of N, N-disubstituted 10 Q formamides

R2b NH

, X

O ^ 15 WV °° r1 (II) or a salt thereof j q j

20 Y 1 X

7 F 1 ·. 25 (I) or a salt thereof

In the above general formulas I and II, R 1, R 1a, R 2b, X and Y have the same meaning as above.

: When the process according to the invention is connected to a known production route, the compounds of the formula III or their salts can advantageously be prepared on an industrial scale.

5 15 7 03

O

Fxr ^ TA ^ C00Rl X? XJ + * 2a "->

Sf

or a salt thereof F

10 (I) or a salt thereof is' NroTJV "°" 1

R2 I X

iir 20 f

F

(lii) or a salt thereof wherein R 1, R 2a, X and Y have the same meaning as above.

It is an object of the present invention to provide a process for the preparation of a 1,4-dihydro-4-oxonapyridine derivative of the formula I or a salt thereof easily and on an industrial scale, which compounds are useful as intermediates in the preparation of an antibacterial drug.

In this specification, the carboxyl protecting group of Rx and R1a belongs to those conventionally used in the art, e.g., the conventional carboxyl protecting groups mentioned in Japanese Patent Application Kokai (not studied) JP 80 665/84, e.g., alkyl, benzyl, pivaloyloxymethyl, trimethylsilyl and the like.

The halogen atom denoting 6 t 'S / O 3 Y is, for example, fluorine, chlorine, bromine or iodine. The C 1-4 alkoxy group of R 2b may be, for example, methoxy, ethoxy, n-propoxy, isobutoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy or dodecyloxy and the like; The C 1-4 alkanesulfonyl group may be, for example, methanesulfonyl or ethanesulfonyl and the like; The C 1-6 alkanesulfonyloxy group may be, for example, methanesulfonyloxy or ethanesulfonyloxy and the like; The di- (C 1-4 alkoxyphosphinyloxy group may be, for example, dimethoxy-10phosphinyloxy, diethoxyphosphinyloxy, dipropoxyphosphinyloxy or dibutoxyphosphinyloxy and the like).

The above-mentioned alkoxy, alkanesulfonyl, benzenesulfonyl, alkanesulfonyloxy, benzenesulfonyloxy, dialkoxyphosphinyloxy and diphenoxyphosphinyloxy groups mentioned above R2b may be substituted by at least one substituent which may be a halogen atom such as fluorine, fluorine, iodine and the like; a nitro group, lower alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 20 sec-butyl, tert-butyl and the like and lower alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n -butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like and other groups.

Suitable N, N-disubstituted formamides of the formula .....: 25 III for the preparation of Vilsmeier reagents are e.g.

N, N-dimethylformamide, such as N, N-dimethylformamide, Ν, Ν-diethylformamide, Ν, Ν-dibutylformamide and the like, and N-formyl nitrogen-containing saturated heterocyclic groups, such as N-formylpyrrolidine , N-formyl-piperidine, N-formylmorpholine, N-formylthiomorpholine and the like, and other groups.

Inorganic halides suitable for the preparation of Vilsmeier reagents include phosphonyl halides such as phosphorus oxychloride and phosphorus oxybromide and the like; and 35 suitable organic halides include carbonyl halides such as phosgene, diphosgene, ethyl chlorocarbonate and the like.

By a salt of all of the above compounds is meant a salt formed with basic groups such as an amino group and the like, or with acidic groups such as a carboxyl group, a hydroxyl group and the like. Salts formed with a basic group include, for example, salts formed 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, trifluoroacetic acid and the like; salts with sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and the like, etc. Salts formed with an acidic group include, 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 as well as nitrogenous organic bases such as procaine, dibenzylamine, N-benzyl-B-phenethylamine, 1-efenamine, N, N-dibenzylethylenediamine, triethylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, Salts of N-methylmorpholine, diethylamine, dicyclohexylamine and the like.

In the process of the invention, a compound of formula II or a salt thereof is reacted with a Vilsmeier reagent in any reaction-inert solvent, e.g. an aromatic hydrocarbon such as benzene, toluene, dichlorobenzene or the like; in a halogenated hydrocarbon such as methylene chloride, chloroform, dichloroethane or the like; in formamide such as N, N-dimethylformamide or the like, etc. These solvents can be used as a mixture of two or more.

8 tb / 03

Once the Vilsmeier reagent is dissolved, it can be used as a solvent. In the reaction, the amount of Vilsmeier reagent used is at least equimolar with respect to the compound of formula II, preferably 2.0 to 5.0 moles per mole of the compound of formula II. The reaction can be usually carried out at 0 to 150 ° C, preferably 0 to 90 ° C for five minutes to 30 hours.

The Vilsmeier reagent derived from Ν, dis-disubstituted formamide can be obtained by reacting N, N-disubstituted formamide with the inorganic or organic halide described above in equimolar amounts, and this Vilsmeier reagent is usually prepared at 0-25 ° C for five minutes to one. hours. The Vilsmeier reagent can also be prepared in situ.

The reaction conditions are not limited to the above, but may be varied depending on the reactants used.

The compound of formula II (includes compounds Ha, Hb, Ile, Ilf and Ilg, which will be shown below) and the compounds of formulas Ha and Ile, which will be shown below, or a salt thereof, can be prepared according to the following preparation routes: 6 5 / 03 9

Production routes 1 0 ° 5 F COOR1 F (il,

-> YoY -------------- ~ VoT 0R

w A M AuA

Y Nil v V Y ΧΝΠ v φτ φτ

F F

<Vh> (Uh) or its salt 1 ° °

F COORX 3 F H H

- yst -lp: w ^ is R5 'mii f 5 r /' N '^ NH y φτ <¥

F F

<vb> (Hb) or a salt thereof, 0 0 F COOR1. F H H.

—R A "4fr ΪΚ ^” "

RbSO- NH v R SO / NH v J I Λ J i Λ Φ "φ ·

F F

(Vc) \ t (Ile) or a salt thereof

V

L b / ϋ 3 ίο 1 I 00 F COOR _A F || || ^ j ^ Y ^ y ^ / ^ or1 c / ^ mA - fi A ^ mA.

5 V R6 S Nil v R S NH χ φ "Φ

F F

(Vd) (lid) 10 or son salt / -> fyVcoor1 h ^ o »1» 6 lil —H lii

R6 SO N Nil v R6 SO NH

φ. φ

20 T F

(Ve) (Ile) k or a salt thereof j '1 Ί oo 25 F COOR1 F 11 | , U W · - U) pX ^ or r6S ° 2 N Nil x R6 SO / N NH χ Φ Φ

30 l F

(Vf) (Ilf) or a salt thereof 35 11 L b 7 O 3 oo F COOR1 E '- 1 1 „la (of (of ji pt F * (Vg), II9> 10 or a salt thereof rs ^ oo F COOR1 \ FY ^ AA0Rla “JK, - * Ä ff 20 (VM« IIa),,, or a salt thereof or a salt thereof 25 N.

B

F - {qV NHCCl2 COOR1 + ^ C ^ COOR1 'n, nh z f x 30 (VI) (vii) or a salt thereof or a salt thereof 35 8 5 7 0 3 12

In the preparation routes described above, R50- is the same alkoxy group as mentioned for R2b; R6SO3- is the same alkanesulfonyloxy or benzenesulfonyloxy group as mentioned for R2b; R6SO2- is the same alkanesulfonyl or benzenesulfonyl group as mentioned for R2b; (R60) 2PO- is the same dialkoxyphosphinyloxy-O or ditenyloxyphosphinyloxy group as mentioned for R2b; R 6 S- is an alkylthio group, for example a (C 1-12) -10 alkylthio group such as methylthio, ethylthio, n-propylthio, isopropylthio, isobutylthio, tert-butylthio, pentylthio, hexylthio, heptylthio, octylthio, dodecylthio or the like, or a phenylthio group; R 6 S- is an alkanesulfinyl group, for example, a (C 1-5) alkanesulfinyl group such as methanesulfinyl, ethanesulfinyl or the like or a benzenesulfinyl group; Z is a leaving group which may be a halogen atom, a hydroxyl group or an optionally substituted acyloxy, alkanesulfonyloxy, arenesulfonyloxy, dialkoxyphosphinyloxy or diaryloxy-phosphinyloxy group; and R 1, R 1a, X and Y are as defined above.

The above manufacturing routes are described in detail below.

1) A compound of formula Va or a salt thereof can be prepared by the publication of British patent GB

. ··. 1 409 987 to react a compound of formula VI or a salt thereof with a compound of formula VII or a salt thereof prepared from Bull. Soc. Chem. Fr., ss. 1165-1169 (1975), J. Chem. Soc. (C) s.

30 2206-2207 (1967) and Program and Abstracts of the 105th

Meeting of the Japanese Pharmaceutical Society, p. 523 (1985).

As the solvent for this reaction, any reaction-inert solvent can be used, e.g., water, alcohols such as methanol, ethanol, isopropyl alcohol, butyl ε 5 7 O 3 13 alcohol, ethylene glycol, methyl saline 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, dimethylcellosolve 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 dimethyl sulfoxide and the like and the like. These solvents can be used as a mixture of two or more.

Condensing agents include, for example, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium hydride, sodium methoxide, sodium ethoxide, potassium methoxide, potassium methoxide and the like.

The amount of the compound of formula VII or a salt thereof used in this reaction is not critical, but must be at least equimolar to the compound of formula VI, preferably 1.0 to 3.0 moles per mole of the compound of formula VI. This reaction is usually carried out at 0 to 150 ° C, preferably 15 to 100 ° C, for five minutes to 30 hours.

• 25 2) Alkylation

A compound of formula Vb or a salt thereof and a compound of formula Hb can be prepared by reacting a compound of formula Va or a salt thereof or a compound of formula Ha or a salt thereof with an alkylating agent in the presence or absence of an acid scavenger, respectively.

Any reaction-inert solvent may be used in the reaction, e.g., water, alcohols such as methanol, ethanol, isopropyl alcohol and the like; ethers such as diethyl ethers, 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, chloroform and the like; amides such as Ν, Ν-dimethylformamide, N, N-dimethylacetamide and the like; sulfoxides such as dimethyl sulfoxide and the like, etc. These solvents may be used as a mixture of two or more. Alkylating agents include, for example, diazoalkanes such as diazomethane, 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 and the like.

When the alkylating agent is a dialkyl sulfate or an alkyl halide, an acid scavenger can be used. Said acid scavengers include, for example, inorganic bases such as alkali metal hydroxide, time carbonate and the like; and amines such as trimethylamine, triethylamine, tributylamine, N-methylpiperidine, N-methylmorpholine, lutidine, collidine, pyridine and the like.

The amount of the dialkyl sulfate or alkyl halide used as the alkylating agent and the amount of the acid scavenger optionally used are at least equimolar to the compound of the formula Va - '25 or a salt thereof or the compound of the formula Ha or a salt thereof, preferably 1.0 to 2.0 moles per mole of said compounds. In this case, the reaction can be carried out usually at 0 to 150 ° C, preferably 0 to 50 ° C for five minutes to 30 hours.

When the alkylating agent is a diazoalkane, it is at least equimolar with respect to the compound of the formula Va or a salt thereof or the compound of the formula IIa or a salt thereof, preferably 1.0 to 1.5 moles per mole of said compounds. In this case, the reaction can be carried out usually at 0 to 50 ° C, preferably 0 to 25 ° C for five minutes to 30 hours.

3) Halogenation

A compound of formula Vh or a salt thereof can be obtained by reacting a compound of formula Va or a salt thereof with a halogenating agent. As the solvent for the reaction, any solvent inert to the reaction can be used, e.g., aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated carbon-10 hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like; amides such as N, N-dimethylacetamide, Ν, Ν-dimethylacetamide and the like, etc. These solvents can be used as a mixture of two or more. Halogenating agents include, for example, phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, phosphorus pentabromide, phosphorus trichloride, thionyl chloride, phosgene and the like, and these substances can be used as a mixture of two or more and can also act as solvents. The amount of halogenating agent used is at least equimolar to the compound of formula Va or a salt thereof. The reaction can be usually carried out at 0 to 150 ° C, preferably 50 to 110 ° C for 30 minutes to 30 hours.

4) Sulfonylation

A compound of formula Vc or a salt thereof and a compound of formula .25 Ile can be obtained by reacting a compound of formula Va or a salt thereof and a compound of formula Ha or a salt thereof, respectively, with a sulfonylating agent in the presence or absence of an acid scavenger. As the solvent, any solvent inert to the reaction can be used, e.g., 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 chloride, chloroform, dichloroethane and the like; 16 t.:. g 3 ketones such as acetone, methyl ethyl ketone and the like; nitriles such as acetonitrile and the like; amides such as Ν, Ν-dimethylformamide, N, N-dimethylacetamide and the like; sulfoxides such as dimethyl sulfoxide and the like, hexamethylphosphoramide, pyridine and the like. These solvents can be used as a mixture of two or more. Sulfonylating agents include, for example, alkanesulfonyl and arenesulfonyl halides such as methanesulfonyl chloride, trifluoromethanesulfonyl chloride, ethanesulfonyl chloride-1-methylethanesulfonyl chloride, 1,1-dimethylethanesulfonyl sulfene, benzene sulfide, benzene. , 4-trichlorobenzenesulfonyl chloride, 2,4,5-trichlorobenzenesulfonyl chloride, 2,4,6-trimethylbenzenesulfonyl chloride, 2,4,6-triisopropylbenzenesulfonyl chloride, naphthalenesulfonyl chloride and the like, alkanesulfonide and arenesulfonyl sulfone methanesulfonic anhydride, toluenesulfonic anhydride and the like, etc. Acid scavengers include, for example, inorganic and organic bases such as triethylamine, diisopropylethylamine, 1,8-diaziazabicyclo [5.4.0] undec-7-ene (DBU), pyridine, ka, etc. -lium tert-butoxide, sodium hydride, alkali hydroxides, alkali carbonates and the like t.

. . The amounts of the sulfonylating agent and any acid scavenger used are at least equimolar with respect to the compound of formula Va or a salt thereof or the compound of formula Ha or a salt thereof, preferably 1.0 to 2.0 moles per mole of said compounds. The reaction can usually be carried out at -10 to 150 ° C, preferably 0 to 80 ° C for five minutes to 30 hours.

5) Thiolation

To prepare a compound of formula IId from a compound of formula IIa or a salt thereof, or a compound of formula

For the preparation of a compound of formula Vd and a compound of formula Vd 17 C b / ΰ 3 or a salt thereof from compounds of formula Vh or Vc or a salt thereof, a compound of formula Uh, Ile,

To react a compound of Vh or Vc or a salt thereof with thiol or a salt thereof, e.g. methanethiol, ethanethiol-5-one, n-propanethiol, 1-methylethanethiol, isobutanethiol, 1,1-dimethylethanethiol, pentanethiol, hexanethiol, with heptane thiol, octanethiol, dodecanethiol, thiophenol, naphthalenethiol or the like in the presence or absence of an acid scavenger. Thiol salts 10 are, for example, salts formed with said acidic groups and the like in connection with a compound of formula (I) or (II). As the solvent used in the reaction, any solvent inert to the reaction can be used, e.g., aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and the like; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like; amides such as N, N-dimethylformamide, N, N-dimethylsetamide and the like; sulfoxides such as dimethyl sulfoxide and the like, etc. These solvents may be used as a mixture of two or more. Acid scavengers include, for example, inorganic bases such as alkali hydroxides, sodium hydride, alkali carbonates and the like; organic bases, such as trimethylamine, triethylamine, diisopropylethylamine, DBU, potassium tert-butoxide, tributylamine, pyridine, N-methylpiperidine, N-methylpiperidine, N-methylmorpholine, lutidine, collidine and the like. The amount of the thiol or a salt thereof and the amount of the acid-binding agent optionally used are at least equimolar with respect to the compound of the formula Uh or Ile or the compound of the general formula Vh or Vc or their salts, preferably 1.0 to 2.0 moles of said compounds. per mole. The reaction can be usually carried out at 0 to 150 ° C, preferably 0 to 70 ° C for five to 30 hours.

ie ίί 7 03 6) Phosphorylation

Compounds of formulas IIg and Vg or their salts can be obtained by reacting compounds of formulas IIa and Va or their salts with a phosphorylating agent, respectively, in the presence or absence of an acid scavenger.

Any solvent inert to the reaction can be used, e.g. in particular the same solvents used in the sulfonylation described above. Phosphoryl phosphorylating agents include, for example, dialkylphosphoryl halides such as dimethylphosphoryl chloride, diethylphosphoryl chloride, dipropylphosphoryl chloride, dibutylphosphoryl chloride and the like; diarylphosphoryl halides such as diphenylphosphoryl chloride and the like and the like.

The acid scavengers used in the reaction are, in particular, the same acid scavengers used in the sulfonylation described above. The amount of the phosphorylating agent to be used and, if appropriate, the amount of the acid-binding agent to be used are at least equimolar with respect to the compound of the formula Ha 20 or Va or a salt thereof, preferably 1.0 to 1.5 moles per mole of said compounds. The reaction can be usually carried out at 0 to 150 ° C, preferably 0 to 50 ° C for five minutes to 30 hours.

7) Oxidation 25 Compounds of formulas Ile and Ilf can be prepared by reacting a compound of formula Ild with an oxidant. under conditions and the compounds of formulas Ve and Vf or their salts can be prepared by reacting a compound of formula Vd with an oxidant. conditions.

As the solvent mentioned above, any solvent inert to the reaction can be used, for example, aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like; ethers such as diethyl ether, tetrahydrofuran E 703, dioxane and the like; fatty acids such as formic acid, acetic acid and the like, water and the like. These solvents can be used as a mixture of two or more. Oxidizing agents include, for example, organic peracids such as perura-5-odoric acid, peracetic acid, perbenzoic acid, m-chloroperbenzoic acid and the like, hydrogen peroxide, periodic acid, sodium metaperiodate, potassium metaperiodate, potassium permanganate, ozone and the like.

Oxidizing agents which are particularly preferred for obtaining a compound of formula 10 or a compound of formula Ve or their salts (sulfoxides) include organic peracids, sodium metaperiodate, potassium metaperiodate and the like, and the amount of oxidant used is 1.0 to 1.2 moles of the compound of formula IId. or per mole of a compound of formula Vd or a salt thereof.

Oxidizing agents which are particularly preferred for obtaining a compound of formula IIf or a compound of formula Vf or their salts (sulfones) include organic peracids, hydrogen peroxide and the like, and the amount of oxidant used is 2.0 to 2.5 moles of the compound of formula IId or formula Vd per mole of the compound or salt thereof. The compound of formula Ile or the compound of formula Ve or a salt thereof may be further oxidized to sulfones, if necessary. These reactions can usually be carried out at 0 to 100 ° C, preferably 0 to 30 ° C for five minutes to 30 hours.

8) Compounds of formulas Ha, Hb, lie, Ilf and Ilg or their salts (i.e. compounds of formula II or their salts) can be obtained from a compound of formula V containing compounds of formulas Va, Vb and Vc, Vf and Vg , wherein R1 is a hydrogen atom, a reactive derivative of a carboxyl group or salts thereof and compounds of formulas Ild, lie and Uh, respectively, or salts thereof can be obtained from a reactive derivative of a carboxyl group of compounds of formulas Vd, Ve and Vh or salts thereof as follows: ί 7 O 3 20

Reactive derivative in the carboxyl group of the compound below:

F ^ C00H

Ä.

F

(V) 10 C00Rla ^ COOR1 * L / C00Rla (viii-1) 2 Ncooh / (VIII-2) or a salt thereof, 0 „__la / or a salt thereof 15 F Ψ" rrTr ^ C00R and decarboxy- Y £ V Ji - ^ COORlb / lolntl χ / & 20 Y /

F

(IX) / or its salt f 25 Carboxyl \ / protecting group \

removal and \ I

decarboxylation \ i

; Y O T

'F CCH-C00Rla

to stay

30 r2 ^ n \ hy ΐ · & T <XI>

F

': (II) or a salt thereof 35 In the above scheme, R1a, R2b and X have the same meaning as above and R1b is a carboxyl protecting group which has the same meaning as the examples mentioned in connection with R1a and which may be the same or different from Rla.

Reactive derivatives formed with the carboxyl group of a compound of formula V include, 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 dinirophenyl ester, cyanomethyl ester, succinimido ester and the like; active acid amides formed with imidazole or the like and the like.

Salts of the compounds of formulas VIII-1 and VIII-2 include, for example, salts with alkali metals such as lithium, potassium, sodium and the like; salts formed with alkaline earth metals such as magnesium and the like, and the like.

The salts of the compound of formula IX are the same as those mentioned as salts of the compound of formula I and the like.

A compound of formula II or IX or a salt thereof can be prepared by reacting a reactive derivative formed with a carboxyl group of a compound of formula V with a compound of formula VIII-2 or a salt thereof or a compound of formula VIII-1 or a salt thereof in a suitable solvent. As the solvent, any solvent inert to the reaction can be used, e.g., alcohols such as methanol, ethanol, isopropyl alcohol and the like; aromatic hydrocarbons such as benzene, toluene and the like; halogenated and 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 Ν, Ν-dimethylformamide, N, N-dimethylacetamide and the like, etc. The amount of the compound of the formula VIII-1 or VIII-2 or a salt thereof is at least equimolar with the carboxyl group of the compound of the formula V 22 <- r; 7 «. "U" relative to a reactive derivative, preferably 1.0-2.5 moles per mole of said derivative. The reaction can be usually carried out at -50 to 100 ° C, preferably -20 to 70 ° C for five minutes to 30 hours.

To convert a compound of formula IX or a salt thereof to a compound of formula II or a salt thereof, a carboxyl protecting group R 1 can be removed from a compound of formula IX or a salt thereof and decarboxylated with trifluoroacetic acid in anisole or p-toluene-sulfonic acid in an aqueous solvent.

In each of the steps described above, the compound obtained may optionally be deprotected in a known manner to give the corresponding free carboxylic acid. The free carboxylic acid may also optionally undergo a salt formation reaction or esterification in a manner known per se to give the corresponding salt or ester.

The compounds obtained by the above-mentioned reactions can be isolated or separated in the usual manner, or they can be used in subsequent reactions without isolation or separation.

The process of the present invention is particularly suitable for industry because the compound of formula I or a salt thereof can be obtained without the reaction taking place via the 2,6-dichloro-5-fluoropyridine derivative which is an intermediate in the processes described in the above-mentioned sources. Abstract of the 24th ICAAC, and in Japanese Patent Application Kokai (not studied) JP 228 479/85 (said derivative causes a drug injury, e.g. rash or the like).

. . The antibacterial activities of typical compounds of general formula III synthesized from intermediates of general formula I of the invention are described below.

According to the standard method of the Japanese Society for Chemotherapy [Chemotherapy, 29 (1), 35 76-79 (1981)], a bacterial solution obtained by culturing bacteria in cardiac infusion ε 5 7 O 3 23 broth (manufactured by Eiken Kagaku) at 37 ° C for 20 hours , were inoculated onto drug-containing cardiac infusion agar and cultured for 20 hours at 37 ° C, after which bacterial growth was monitored to detect a minimum concentration at which bacterial growth was inhibited. This concentration is abbreviated as MIC (pg / ml). The number of inoculated bacteria was 104 cells / dish (106 cells / ml). The MIC values of the test compounds listed below are shown in Table 1.

10 Table 1 n »" 15 /

nh2 * hci lOJ

F

Bacteria —--- F H

20 -

St. aureus FDA209P SO, 05 SO, 05

St. equidermidis IID886 SO, 05 0.1

St. aureus F-137 * SO, 05 0 * 1 E. coli NIHJ SO, 05 SO.05 25--1--1- • 'E. coli TK-111 SO, 05 SO, 05 E. coli GN 5 4 8 2 * * SO .05 <0.05

Ps. Aeruginosa S-68 0.2 0.2 3Q Aci. anitratus A-6 SO, 05 SO, 05

Ps. Aeruginosa IF03445 0.2 0.2

Ps. Aeruginosa GN918 ** 0.1 0, .1 ... 35 x penicillinase-producing bacterium xx cephalosporinase-producing bacterium t; ί 7 O 3 24

When a compound of formula III or a salt thereof is used as a drug or medicament, it is suitably mixed with carriers conventionally used in pharmaceutical preparations, and tablets, capsules, powders, syrups, granules, suppositories, ointments, injections and the like are prepared in a similar manner. The route of administration, dosage, and frequency of administration may be varied as appropriate for the patient's symptoms, and the adult is usually administered orally or parenterally (e.g., by injection, drip, rectal) in an amount of 0.1 to 100 mg / kg / day in one or more doses.

The following reference examples and examples illustrate the invention and are intended to illustrate the present invention.

The following abbreviations are used in the Reference Examples and Examples:

Me = methyl group

Et = ethyl group 20 i-Pr = isopropyl group

Example 1 (1) 250 mg of phosphorus oxychloride was added dropwise under ice-cooling to 4 ml of N, N-dimethylformamide, and after stirring for 10 minutes at the same temperature, 200 mg of ethyl 2- [2- (2,4-difluorophenylamino) -5-fluoro was added. -6-methoxynicotinoyl acetate. The resulting mixture was allowed to react for 3.5 hours at 50-60 ° C. The reaction mixture was poured into 50 ml of ice water, 20 ml of chloroform was added, and the organic layer was isolated, washed with 20 ml of water, and then dried over anhydrous magnesium sulfate.

The solvent was removed by distillation under reduced pressure, and 5 ml of diethyl ether was added to the residue thus obtained, and the crystals were then isolated by filtration to give 150 mg (yield 72.2%) of ethyl 7-chloro-6-fluoro-1- (2,4-difluoro-35-phenyl). ) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, m.p. 217-220 ° C. The compound was recrystallized from a mixture of acetone and methanol (1: 1 by volume) to give crystals with a melting point of 219-221 ° C. Elemental analysis values for C 17 H 10 N 2 O 3 ClF 3 Calculated (%): C 53.35, H 2.63, N 7.32 5 Found (%): C 53.61, H 2.47, N 6.96 (2) Repeat the same procedure as in (1) starting from the starting compounds shown in Table 2 and the target compound shown in Table 2 was obtained in the yields shown in Table 2.

10 0 Table 2

Il 0 FVVCCH2COOEt Fv ~ JLC00Et

R27 ° 7nH f -> C1- ^ V F

15 C ° 7 φΓ _ £ ____ F_ Starting compound: Yield of target compound R2b _ (% ^ _ 20 HO- 88j9

MeSO3-96.6

Me '25 Me- ^ O ^ -SO3- 84 f 8

Ma (EtO) 2 | 84 - 84.6

7 '' O

30 ---

76r 9 O

EtSO0- 76.5 35 _f__ <O> -SO2- 78.9 26 and 5,703

The physical values of the target compound and the compound obtained in (1) above were identical.

(3) The same procedure as in (1) above was repeated using ethyl 2- [2- (4-fluorophenylamino) -5-fluoro-6-hydroxynicotinoyl] acetate to give ethyl 7-chloro-1- (4-fluorophenyl). ) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, yield 74.9%. Sp. 230-232 eC (recrystallized from acetone).

IR (KBr) cm -1: δ 1730, 1700 NMR (CDCl 3) δ 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) Elemental analysis values: C 17 H 11 N 2 O 3 ClF 2 Calculated (%): C 55.98, H 3.04, N 7.68 Obtained (%): C 56.09, H 2.92, N 7.68 (4) The same procedure as in (1) above was repeated except that the phosphorus oxychloride was replaced by one of the halides shown in Table 3 and obtained in Table 3. results presented.

20 Table 3 25 MeO ^ Vr Hydrogenide ^ <* "1 /

(o / ^ C ° J

: _______ T __! _

Halide (amount charged) Amount of target compound obtained (yield) 30 Diphosgene (160 mg) 150 mg (72.2%)

Phosphorus pentachloride (340 mg) 145 mg (69.8%)

Phosphorus dichloride (225 mg) 125 mg (60.1% J

... 35 27 65703

The the physical values of the target compounds and the compound obtained in (1) above were identical.

Example 2 (1) 130 mg of Ν, Ν-dimethylformamide was dissolved in 2 ml of 1,2-dichloroethane, 270 mg of phosphorus oxychloride was added dropwise under ice-cooling, and then the resulting mixture was allowed to react for 10 minutes at the same temperature. Then, 200 mg of ethyl 2- [2- (2,4-difluorophenylamino) -5-fluoro-6-methoxycinicotinoyl] acetate was added to the reaction mixture, and the resulting mixture was allowed to react for 4.5 hours at reflux temperature. The reaction mixture was poured into 30 ml of water, and then 30 ml of chloroform was added thereto. The organic layer was then isolated, washed 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 the residue thus obtained was purified by column chromatography [Wa-ko Silica Gel C-200, eluent benzene-ethyl acetate 20 (10: 1 by volume)] to give 130 mg (yield 62.6%) of ethyl 7-chloro- 1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate. The physical values of this compound and the compound obtained in Example 1 were identical.

(2) The same procedure as in (1) above was repeated except that Ν, Ν-dimethylformamide was replaced with 160 ml of N-formylpyrrolidine to give 135 mg (yield 65.0%) of ethyl 7-chloro-1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate. The physical values of this compound and the compound obtained in Example 1 (1) were identical.

Example 3

Suspended in 10 ml of concentrated hydrochloric acid - 500 mg of ethyl 7-chloro-1- (2,4-difluorophenyl) -6-fluoro-. 35 l of 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate and fc C 7 03 28 formed were allowed to react for one hour at reflux temperature. The reaction mixture was diluted with 10 ml of water, and the crystals thus precipitated were isolated by filtration, and then washed with 2 ml of water to give 450 mg (yield 97.1%) of 7-chloro-1- (2,4-difluorophenyl) -6-fluorine. -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, m.p. 238-242 ° C. Melting point 242.5-243.5 ° C [recrystallized from chloroform-ethanol (2: 1 by volume)]. Reference Example 1 10 (1) 50 g of ethyl 6-imino-8-phenoxypropionate hydrochloride and 27.8 g of 2,4-difluoroaniline were suspended in 300 ml of ethyl acetate, and the resulting suspension was allowed to react at reflux temperature for two hours. The precipitated crystals were isolated by filtration and washed with two 200 ml portions of ethyl acetate to give 47 g (yield 82.2%) of ethyl N- (2,4-difluorophenyl) amidinoacetate hydrochloride, m.p. 196-197 ° C.

IR (KBr) cm -1: ν max 1730 NMR (DMSO-DJ δ values: 1.26 (3H, t, J = 7 Hz), 4.07 (2H, 20 s), 4.19 (2H , q, J = 7 Hz), 7.02-7.78 (3H, m), 9.11 (1H, bs), 10.26 (1H, bs), 12.28 (1H, bs).

The following compounds were obtained in the same manner as above: Methyl N- (2,4-difluorophenyl) amidinoacetate hydrochloride, m.p. 192-193 ° C, IR (KBr) cm -1: ν max 1735, NMR δ (DMSO-d 6) δ values: 3.74 (3H, s), 4.09 (2H, s), δ, 91-7.73 (3H, m), 9.15 (1H, bs), 10.31 (1H, bs), 12.29 (1H, bs). Methyl N- (4-fluorophenylamidinoacetate hydrochloride, mp 134-135 ° C, IR (KBr) cm -1: ν max 1730, NMR (DMSO-d 6) δ values: 3.74, (3H, s), 4, Δ (2H, s), 7.01-7.59 (4H, m), 8.96 (1H, bs), 10.06 (1H, bs), 12.26 (1H, bs).

(2) 23.0 g of methyl N- (2,4-difluorophenyl) amidinoacetate hydrochloride was dissolved in a mixture of 92 ml of water and 92 ml of methylene chloride, and the pH of the solution was adjusted to 13 with 2N aqueous sodium hydroxide solution. After this, the organic layer was isolated, washed successively with 50 ml of water and 50 ml 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 α-formyl-α-fluoroacetate at room temperature, the resulting mixture was allowed to react at reflux for 4 hours, and then 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 precipitated were isolated by filtration. The crystals thus obtained were suspended in 184 ml of water, the pH of the suspension was adjusted to 1.0 with 6N hydrochloric acid, 46 ml of water and 46 ml of isopropyl alcohol were added to the crystal thus obtained, then the crystals were isolated by filtration to give 15.0 g (yield 57.9%). ) methyl 2- (2,4-15 difluorophenylamino) -5-fluoro-6-hydroxynicotinate, m.p. 222-223 ° C (recrystallized from ethyl acetate).

IR (KBr) cm -1: Vc δ 1700, NMR (TFA-dJ δ values: 4.06 (3H, s), 6.71-7.65 (3H, m), 8.12 (1H, d, J = 11 Hz) The following compounds were obtained in the same manner as above: Ethyl 2- (2,4-difluorophenylamino) -5-fluoro-6-hydroxynicotinate, mp 177-178 ° C (recrystallized from ethyl acetate), IR (KBr) cm -1: λ max, 1700, NMR (TFA-dx) δ values: 1.52 (3H, t, J = 7 Hz), 4.50 (2H, q, J = 7 Hz), 6.80-7.65 (3H, d, J = 11 Hz), 8.15 (1H, d, J = 11 Hz).

‘25 Methyl 5-fluoro-2- (4-fluorophenylamino) -6-hydroxynicotinate, m.p. 227-228 ° C (recrystallized from ethyl acetate), IR (KBr) cm -1: Vc-o 1690, NMR (TFA-di) δ values: 4.05 (3H, s), 6.89-7.53 (4H, m), 8.11 (1H, d, J-11 Hz).

(3) To a mixture of 5 ml of water and 5 ml of methylene chloride was dissolved 500 mg of methyl N- (2,4-difluorophenyl) amidinoacetate hydrochloride, and the pH of the resulting solution was adjusted to 13.0 with 2N aqueous sodium hydroxide solution. The organic layer was isolated and washed successively with 3 ml of water and 3 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium S / 03 sulfate. To this solution were added 820 mg of ethyl 3- (4-methylbenzenesulfonyloxy) -2-fluoroacrylate, followed by 120 mg of sodium methoxide (purity 92.3%) and 5 ml of methanol at room temperature, and then the resulting mixture was allowed to react for 24 hours at the same temperature. The solvent was then removed by distillation under reduced pressure, and 10 ml of water and 2 ml of ethyl acetate were added to the residue thus obtained. The pH of the resulting solution was adjusted to 1.0 with 6N hydrochloric acid, the precipitated crystals were isolated by filtration and washed successively with 2 ml of water and 2 ml of isopropyl alcohol to give 370 mg (yield 65.7%) of methyl 2- (2,4-difluoro-phenylamino) -5-fluoro-6-thia-hydroksinikotinaat. The physical values of this compound and the compound obtained in (2) above were identical.

(4) The procedure of (3) was repeated except that ethyl 3- (4-methylbenzenesulfonyloxy) -2-fluoroacrylate was replaced by one of the 3-substituted-2-fluoroacrylates listed in Table 4. The results obtained 20 are shown in Table 4.

31 85703

Table 4 H \ c ^ C = C-C00Et, NaOMe ö Z F FY ~ yC00Me

F - (oV "NHCCH 2 COOMe -> 12 A

Il 2 HO N NH _ F NH Γ7 ψ

10 F

Compound Yield Z (%) 15 MeSO 3 -41.7

O

/ —V N

(\ Oj-0) 2PO- 50.7

O

20 / —v II

mV · CO- 44.4 ·: · 25

In each case, the physical values of the compounds obtained and the compound obtained in (2) above were identical.

Reference Example 2 200 mg of methyl 2- (2,4-difluorophenylamino) -5-fluoro-6-hydroxynicotinate were dissolved in 6 ml of tetrahydrofuran, and a solution of about 40 mg of diazomethane was added to the resulting solution under ice-cooling. in diethyl ether, and then the resulting mixture was allowed to react for 30 minutes at room temperature. To this residue was added so much acetic acid that the reaction mixture ceased to foam and then the solvent was removed by distillation under reduced pressure. The crystals thus obtained were washed with 6 ml of isopropyl alcohol to give 150 mg of 5- (yield 71.6%) methyl 2- (2,4-difluorophenylamino) -5-fluoro-6-methoxynicotinate, m.p. 160-161 ° C. Sp. 160.5-161.5 ° C (recrystallized from ethyl acetate), IR (KBr) cm -1: c, 0 1690, NMR (CDCl 3) δ values: 3.89 (3H, s), 3.98 (3H, s), 6.57-7.08 (2H, m) 7.81 (1H, d, J = 11 Hz), δ 8.10-8.97 (1H, m), 10.24 (1H, bs ).

Reference Example 3

200 mg of methyl 2- (2,4-difluorophenylamino) -5-fluoro-6-hydroxynicotinate were dissolved in 5 ml of N, N-dimethylformamide, and 110 mg of potassium carbonate and 93 mg of dimethyl sulfate were added to the resulting solution at room temperature. and then the resulting mixture was allowed to react for two hours at the same temperature. Then, 20 ml of water and 20 ml of ethyl acetate were added to the reaction mixture, then the organic layer was isolated and 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 evaporated by distillation under reduced pressure, 5 ml of isopropyl alcohol was added to the thus obtained crystalline material, and the crystals were isolated by filtration to give 180 mg (yield 86.0%) of methyl 2- (2,4-difluorophenylamino) -5-fluoro. -6-metoksini-kotinaattia. The physical values of this compound and the compound obtained in Reference Example 2 were identical.

. . Reference Example 4 200 mg of methyl 2- (2,4-difluorophenylamino) -5-fluoro-6-hydroxynicotinate were dissolved in 5 ml of N, N-dimethylformamide, and 110 mg of potassium carbonate and 0.11 g of methyl iodide were added at room temperature. and then the resulting mixture was allowed to react for one hour at the same temperature. To the reaction mixture were added 20 ml of water and 20 ml of ethyl acetate, the organic layer was isolated and 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 then 5 ml of isopropyl alcohol was added to the thus obtained crystalline material, and the crystals were isolated by filtration to give 190 mg (yield 90.7%) of methyl 2- (2,4-difluorophenylamino) -5-fluoro-6-methoxynicotinate. . The physical values of this compound and the compound obtained in Reference Example 10 2 were identical.

Reference Example 5

A mixture of 9.5 g of methyl 2- (2,4-difluorophenylamino) -5-fluoro-6-hydroxynicotinate, 26.5 g of phosphorus pentachloride and 46.9 g of phosphorus oxychloride was reacted for four hours. At -80 eC. The reaction mixture was then added in small portions to 285 ml of water, and the crystals thus precipitated were isolated by filtration and then washed with 57 ml of water. The crystals thus obtained were purified by column chromatography (Wako Silica Gel C-200, eluent: to-20 I / l) to give 3.5 g (yield 34.7%) of methyl 6-chloro-2- (2,4-difluorophenylamino). -5-fluoronicotinate, m.p.

137-139 ° C. Sp. 139.5-140.5 ° C (recrystallized from diisopropyl ether), IR (KBr) cm -1: C.Q 1695, NMR

(CDCl 3) δ values: 3.93 (3H, s), 6.61-7.06 (2H, m), 7.94 (1H, 25 d, J = 9 Hz), 8.15-8, 57 (1 H, bs).

Reference Example 6

500 mg of methyl 2- (2,4-difluorophenylamino) -5-fluoro-6-hydroxynicotinate were suspended in 10 ml of methylene chloride, 440 mg of 2,4,6-trimethylbenzenesulfonyl chloride and 220 mg of triethylamine were added to the resulting suspension, followed by the mixture was allowed to react for three hours at room temperature. To this solution was added 15 ml of water, and the organic layer was isolated, washed with 15 ml of water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation at 34 ° C under reduced pressure, 15 ml of diethyl ether was added to the thus obtained crystalline material, and the crystals were isolated by filtration to give 660 mg (yield 81.9%) of methyl 2- (2,4-difluorophenylamino) -5-fluoro. -6- (2,4,6-trimethyl-5-benzenesulfonyloxy) nicotinate, m.p. 153-155 ° C.

Sp. 155-156 ° C (recrystallized from ethyl acetate), IR (KBr) cm -1: Vc 1700 / N "1 * (CDCl 3) δ values: 2.33 (3H, s), 2.59 (6H, s), 3.92 (3H, s), 6.32-6.84 (2H, s), 7.35-7.94 (1H, m), 8.05 (1H, d, J = 9 Hz); ), 10.17 (1 H, bs).

The following compounds were obtained in the same manner as above.

Methyl 2- (2,4-difluorophenylamino) -5-fluoro-6-methanesulfonyloxycotinate, m.p. 120-121 ° C (recrystallized from ethyl acetate), IR (KBr) cm -1: C.Q

1690, NMR (CDCl 3) δ values: 3.30 (3H, s), 3.94 (3H, s), 6.60-7.15 (2H, m), 7.73-8.33 ( m) Ί (2H)

8.07 (d, J = 9 Hz) J

10.00 (1 H, bs).

Ethyl 2- (2,4-difluorophenylamino) -5-fluoro-6- (2,4,6-triisopropylbenzenesulfonyloxy) nicotinate, mp 147-148 ° C (recrystallized from ethyl acetate), IR (KBr) cm 1: c '1700, NMR (CDCl 3) δ values: 1.21 (12H, d, J = 7 Hz), 1.28 (6H, d, J-7 Hz), 1.40 (3H, t, J = 7 Hz), 2.55-3.30 (1H, 25 m), 3.70-4.60 (m) 1 (4H)

4.73 (q, J-7 Hz) J

6.20-7.30 (m) 7.20 (s) J (4H) 3 O 7.50-8.30 (m)> 8.10 (d, J-9 Hz) J (2H) 10.33 (1H, bs).

Reference Example 7

Suspended in 7 ml of N, N-dimethylformamide 35 700 mg of methyl 6-chloro-2- (2,4-difluorophenylamino) -5-35

Lb / 03

fluoronicotinate and 340 mg of triethylamine and 210 mg of ethanethiol were added to the resulting suspension at room temperature, and then the resulting mixture was allowed to react for four hours at 50 ° C. Then, 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 2N hydrochloric acid. The organic layer was isolated, washed successively with 20 ml of water and 20 ml of saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and 10 ml of hexane was added to the thus obtained crystalline material, then the crystals were isolated by filtration to give 620 mg (yield 81.9%) of methyl 6-ethylthio-2- (2,4-difluorophenylamino). -5-fluoronicotinate, m.p. 113-114 ° C. M.p. 113.5-15 114 ° C (recrystallized from diisopropyl ether), IR

(KBr) cm -1: ν max 1680, NMR (CDCl 3) δ values: 1.29 (3H, t, J-7 Hz), 3.07 (2H, q, J = 7 Hz), 3.90 (3H, s), 6.50-7.20 (2H, m), 7.66 (1H, d, J-10 Hz), 7.80-8.50 (1H, m), 10.00 ( 1H, bs).

Methyl 2- (2,4-difluorophenylamino) -5-fluoro-6-phenylthionicotinate was obtained in the same manner as above, m.p. 128-128.5 ° C (recrystallized from diisopropyl ether), IR (KBr) cm -1: λ max 1685, NMR (CDCl 3) δ values: 3.90 (3H, s), δ 6.0 -8.0 (m) δ 7.77 (d, J = 10 Hz) J (9H) 10.25 (1H, bs).

Reference Example 8

3.89 g of methyl 2- (2,4-difluorophenylamino) -5-fluoro-6- (mesitylenesulfonyloxy) nicotinate were dissolved in 39 ml of N, N-dimethylformamide and 1.34 g of thiophenol and 1.23 g of triethylamine were added to the resulting solution. and then the resulting mixture was allowed to cool for 5 hours at room temperature, then 120 ml of ethyl acetate and 36,70703 of 120 ml of water were added to the reaction mixture, and the pH of the mixture was adjusted to 2.0 with 2N hydrochloric acid The organic layer was isolated, washed successively with 80 ml of water and 80 ml. The solvent was removed by distillation under reduced pressure, and 20 ml of n-hexane was added to the crystalline substance thus obtained, and the crystals thus precipitated were isolated by filtration to give 2.85 g (yield 90.2%) of a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. ) methyl 2- (2,4-difluorophenylamino) -5-fluoro-6-phenylthionicotinate 10, mp 126-128 ° C. The physical values of the obtained compound were identical.

In the same manner as methyl 2- (2,4-difluorophenylamino) -6-ethylthio-5-fluoronicotinate was obtained. The physical values of this compound 15 and the compound obtained in Reference Example 7 were identical.

Reference Example 9

3.00 g of methyl 2- (2,4-difluorophenylamino) -5-fluoro-6-hydroxynicotinate (20) were suspended in 30 ml of methanol, and 16.1 ml of 2N aqueous sodium hydroxide solution was added at room temperature, and then the resulting mixture was allowed to react for four hours. hours at reflux temperature. The reaction mixture was then added to a mixture of 60 ml of ethyl acetate and 60 ml of water, and the aqueous layer was isolated. The aqueous layer was adjusted to pH 1.0 with 6N hydrochloric acid, and the crystals thus precipitated were isolated by filtration, washed successively with 15 ml of water and 15 ml of isopropyl alcohol to give 2.68 g (yield 93.7%) of 2- (2,4-difluorophenylamino). ) -5-fluoro-6-hydroxy-30 nicotinic acid, m.p. 213-216 ° C. Sp. 215-216 ° C [recrystallized from acetone-ethanol (1: 1 by volume)], IR (KBr) cm -1: c.0 1700, NMR (DMSO-d 6) δ values: 6.65-7.58 T · (2H, m), 7.86 (1H, d, J-11 Hz), 8.12-8.68 (1H, m), 10.49 (1H, bs).

In a similar manner to the above, 5-fluoro-2- (4-fluorophenylamino) -6-hydroxynicotinic acid, m.p. 216-37 bti 0 3 217 ° C [recrystallized from acetone-methanol (1: 1 by volume)], IR (KBr) cm -1 1685, (shoulder) NMR (DMSO-d 6) δ values: 6.84 -7.94 (5H, m), 10.33 (1H, bs).

Example 10 5.00 g of methyl 2- (2,4-difluorophenylamino) -5-fluoro-6-methoxynicotinate were dissolved in 60 ml of tetrahydrofuran, and 25.5 ml of 1N aqueous sodium hydroxide solution was added at room temperature, followed by stirring. was allowed to react for seven hours at reflux-10 temperature. The solvent was then removed by distillation under reduced pressure, and 100 ml of ethyl acetate and 100 ml of water were added to the residue thus obtained, and then the pH of the resulting mixture was adjusted to 2.0 with 2N hydrochloric acid. The organic layer was washed successively with 50 ml of saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, 10 ml of diethyl ether was added to the crystalline substance thus obtained, and the crystals were isolated by filtration to give 1.40 g (yield 73.3%) of 2-20 (2,4-difluorophenylamino) -5-fluoro-6-methoxynicotine. acid, m.p. 237-240 ° C. Sp. 239-240 ° C (recrystallized from acetone), IR (KBr) cm -1: Vc-o 1665, (DMSO-d 6) δ values: 3.98 (3H, s), 6.76-7, 48 (2H, m), 7.86 (1H, d, J = 11 Hz), 8.10-8.60 (1H, m), 10.51 (1H, bs).

The following compounds were obtained in the same manner as above: 6-chloro-2- (2,4-difluorophenylamino) -5-fluoronicotinic acid, m.p. 226-228 ° C (recrystallized from benzene), IR (KBr) cm -1: ft \ /c.0 1680, NMR (acetone-d 6) δ values: 6.60-7.41 (2H, m), 7.90-850 (m) δ 8.10 (d, J = 9 Hz) J (2H) 10.30 (1H, bs), 10.64 (1H, bs).

2- (2,4-Difluoro-phenylamino) -5-fluoro-6- (2,4,6-trimethyl-benzenesulfonyloxy) -nicotinic acid, m.p. 179-180 ° C (recrystallized from benzene), IR (KBr) λ max 35 1665, NMR (acetone-d 6) δ values: 2.32 (3H, s), 2.55 38

liVQZ

(6H, s), 6.37-8.52 (m) ^ 7.05 (s) (7H)

8.24 (d, J = 9 Hz) J

Δ 10.37 (1H, bs).

2- (2,4-Difluorophenylamino) -5-fluoro-6- (2,4,6-triisopropylbenzenesulfonyloxy) nicotinic acid, m.p. 163.5-164.5 ° C (recrystallized from benzene), IR (KBr) cm -1: c.0 1675, NMR (CDCl 3 -DMSO-d 6) δ values: 1.22 (12H, d, 10 3 = 7 Hz), 1.30 (6H, d, 3 = 7 Hz), 2.55-3.30 (1H, m), 3.70-4.40 (2H, m), 6.20-8.30 (m) Λ 7.22 (s) J (6H)

8.18 (d, 3 = 9 Hz) J

Δ 10.57 (1H, bs).

6-ethylthio-2- (2,4-difluorophenylamino) -5-fluoronicotinic acid, m.p. 209-210 ° C (recrystallized from benzene), IR (KBr) cm -1: CQ 1665, NMR (acetone-d 6) δ values: 1.30 (3H, t, J = 7 Hz), 3.14 ( 2H, q, J = 7 Hz), 6.70-7.50 (2H, 20 m), 7.60-8.50 (m) 7.80 (d, J = 9 Hz) J (2H) 9 .70 (1H, bs), 10.27 (1H, bs).

2- (2,4-difluorophenylamino) -5-fluoro-6-phenylthionicotinic acid, m.p. 264-265 ° C [recrystallized from ethyl acetate-ethanol (1: 2 by volume)], IR (KBr) cm -1: c.0 1660, NMR (DMSO-d 6) δ values: 6.00-7.73 ( Δ H, m), 7.85 (1H, d, J = 10 Hz), 10.58 (1H, bs).

Reference Example 11 30.00 g of 2- (2,4-difluorophenylamino) -5-fluoro-6-methoxynicotinic acid were suspended in 150 ml of methylene chloride, 5.98 g of thionyl chloride and three drops of Ν, Ν-dimethylformamide and then the resulting mixture was allowed to react for two hours at reflux temperature. Excess solvent and thionyl chloride were removed by distillation under reduced pressure (39> 5,703), and 10 ml of n-hexane was added to the crystalline material thus obtained, the crystals were isolated by filtration to give 4.87 g (yield 91.7%) of 2- (2,4-difluorophenylamino) - 5-fluoro-6-methoxynicotinoyl-5 chloride, m.p. 153-154 eC. Sp. 154-155 ° C (recrystallized from methylene chloride), IR (KBr) cm -1: 1 J CmQ 1680, NMR (CDCl 3) δ values: 3.98 (3H, s), 6.60-7.10 (2H , m), 7.70-8.30 (m) Ί 8.06 (d, J = 10 Hz 9 J (2H) 10 The compounds shown in Table 5 were obtained in the same manner as above.

40 ίί 703% in —n - o n - .. -. ♦, x o - 4j tn oo <n ro m £ 0 I II V m> - in ^> -) ·> · -

U S m ro K

(0 io '- I CM

1 - r- Ό - o - _

N 10, - X

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Reference Example 12

Dissolved in 10 ml of methylene chloride 500 mg

2- (2,4-Difluorophenylamino) -5-fluoro-6- (mesitylenesulfonyloxy) nicotinoyl chloride and to the resulting solution was added dropwise at -20 ° C 1 ml of a methylene chloride solution containing 77 mg of imidazole and 120 mg of triethylamine, and then the resulting mixture was allowed to react for 30 minutes at room temperature. Then, 5 ml of water was added to the reaction mixture, and the pH of the mixture was adjusted to 2.0 with 2N hydrochloric acid. The organic layer was isolated, washed successively with 5 ml of saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and 2 ml of diisoisopropyl ether was added to the thus obtained crystalline material, then the crystals were isolated by filtration to give 485 mg (yield 91.1%) of 1- [2- (2,4-difluorophenylamino) - 5-Fluoro-6- (mesitylenesulfonyloxy) nicotinoyl] imidazole, mp 98-101 ° C. Sp. 103-105 ° C [recrystallized from diisopropyl ether-diethyl ether 20 (5: 2 by volume)], IR (KBr) em 16 Vc-o 1670, NMR

(CDCl 3) δ values: 2.33 (3H, s), 2.60 (6H, s), 6.35-8.15 (9H, m), 9.60 (1H, bs).

: The compounds shown in Table 6 were obtained in the same manner as above.

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Reference Example 13

200 mg of 2- (2,4-difluorophenylamino) -5-fluoro-6-methoxycinothinoyl chloride were dissolved in 7 ml of anhydrous tetrahydrofuran, and 1 ml of anhydrous tetrahydrofuran was added dropwise to the resulting solution at -20 to -10 ° C. a solution of furan in 45 mg of imidazole and 65 mg of triethylamine, and then the resulting mixture was allowed to react for 30 minutes at room temperature. Then, 150 mg of magnesium ethoxycarbonyl-10-carbonyl acetate was added to the mixture at room temperature, the resulting mixture was allowed to react for 30 minutes at reflux temperature, and then 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 2N hydrochloric acid. The organic layer was isolated, 5 ml of water was added thereto, and then its pH was adjusted to 7.5 with saturated aqueous sodium hydrogencarbonate solution. The organic layer was isolated, 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, 1 ml of diisopropyl ether was added to the thus obtained crystalline material, then the crystals were isolated by filtration to give 190 mg (yield 81.7%) of ethyl 2- [2- (2,4-difluorophenylamino). ) -5-fluoro-6-methoxynicotinoyl] acetate, 25 m.p. 148-149 ° C, m.p. 149-150 ° C (recrystallized from Bentene), IR (KBr) cm -1 1700, NMR (CDCl 3 δ values: 1.30 (3H, t, J = 7 Hz), 3.90 (2H, s ), 4.02 (3H, s), 4.27 (2H, q, J <7 Hz), 6.65-7.35 (2H, m), 7.73 (1H, d, J = 10 Hz) ), 7.73 (1H, d, J-10 Hz), 7.90-8.40 (1H, m), 11.19 (1H, bs).

The procedure of Reference Examples 11 and 13 was repeated to give the compounds shown in Table 7.

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Reference Example 15

200 mg of 1- [2- (2,4-difluorophenylamino) -5-fluoro-6- (mesitylenesulfonyloxy) nicotinoyl] imidazole were dissolved in 4 ml of anhydrous tetrahydrofuran, 90 mg of magnesium ethoxycarbonyl acetate was added, and then the resulting mixture was allowed to react for 20 minutes. At 50-60 ° C. The reaction mixture was then added to a mixture of 10 ml of ethylene acetate and 10 ml of water, and the pH of the mixture was adjusted to 2.0 with 2N hydrochloric acid. The organic layer 10 was isolated, 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 1 ml of diethyl ether was added to the thus obtained crystalline material, and the crystals were isolated by filtration to give 175 mg (yield 84.2%) of ethyl 2- [2- (2,4-difluorophenylamino) -5-fluoro. - 6- (mesitylenesulfonyloxy) nicotinoyl] acetate. The physical properties of this compound and the compound obtained in Reference Example 14 were identical.

The following compounds were obtained in the same manner as above.

Ethyl 2- [2- (2,4-difluorophenylamino) -5-fluoro-6-methoxynicotinoyl] acetate

Ethyl 2- [2- (2,4-difluorophenylamino) -6-ethylthio-5-fluoronicotinoyl] acetate

Ethyl 2- [2- (2,4-fluorophenylamino) -5-fluoro-6-phenylthiicotinoyl] acetate.

The physical values of these compounds and the corresponding compounds obtained in Reference Examples 13 and 14 were identical.

Reference Example 16. (1) 2.34 g of 2- (2,4-difluorophenylamino) -5-fluoro-6-hydroxynicotinic acid were suspended in 94 ml of anhydrous tetrahydrofuran, 2.00 g of N, N'-carbonyldiimidazole was added under ice-cooling. and then the resulting mixture was allowed to react for two hours at room temperature. Then, 3.50 g of magnesium ethoxycarbonyl acetate was added to the reaction mixture, the mixture was allowed to react for 1.5 hours at reflux temperature, then the reaction mixture was added to a mixture of 150 ml of ethyl acetate and 150 ml of water, and the pH was adjusted to 2.0 with 6N hydrochloric acid. The organic layer was isolated and washed successively with 80 ml of saturated aqueous sodium hydrogencarbonate solution and 80 ml of water, then adjusted with 80 ml of water and adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was isolated, 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, 8 ml of diethyl ether was added to the thus obtained crystalline material, then the crystals were isolated by filtration to give 1.93 g (yield 66.2%) of ethyl 2- [2- (2,4-difluorophenylamino) - 5-fluoro-6-hydroxynicotinoyl lyacetate, m.p. 161-162 ° C. Sp. 161.5-162 ° C (recrystallized from benzene), IR (KBr) cm-1 17c, 1665, NMR (CDCl 3) δ values: 1.29 (3H, t, J = 7 Hz), 3.74 (2H, s), 4.20 (2H, q, J = 7 Hz), 6.57-7.69 (4H, m), 10.17 (1H, bs), 11.52 (1H) , bs).

In a similar manner to the above, ethyl 2- [5-fluoro-2- (4-fluorophenylamino) -6-hydroxynicotinoyl] acetate was obtained, m.p. 185 ° C (decomposes) (recrystallized from ethyl acetate), IR (KBr) cm -1: λ / c.0 1715, 1685, NMR (CDCl 3) δ values: 1.30 (3H, t, J = 7 Hz) , 3.75 (2H, s), 4.25 (2H, q, J * 7 Hz), 7.08-7.34 (4H, m), 7.48 (1H, d, J = 11 Hz) , 11.86 .30 (1H, bs).

(2) The procedure of (1) was repeated except that the reaction temperature and reaction time were changed to 60 ° C and three hours, respectively, to give ethyl 2- [2- (2,4-difluorophenylamino) -5-fluoro-6- hydroxynicotinoyl - ***: 35 lye acetate, yield 34.5%.

('Γ' O 7

4g - 'U O

Reference Example 17

700 mg of 6-chloro-2- (2,4-difluorophenylamino) -5-fluoronicotinic acid were dissolved in 30 ml of anhydrous tetrahydrofuran, 1.13 g of Ν, Ν'-carb-5-carbonyldiimidazole were added under ice-cooling, and then the resulting the mixture was allowed to react for six hours at room temperature. Then, 990 mg of magnesium ethoxycarbonyl acetate was added, the resulting mixture was allowed to react for two hours at 55 ° C, and the reaction mixture was added to a mixture of 75 ml of ethyl acetate and 65 ml of water. The pH of the mixture was adjusted to 2.0 with 6N hydrochloric acid. The organic layer was isolated, 30 ml of water was added, and the pH of the mixture was adjusted to 7.5 with saturated aqueous sodium hydrogencarbonate solution. The organic layer was isolated, 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 column chromatography (Wako Silica Gel C-200; eluent benzene) 2 to give 680 mg (yield 78.9%) of ethyl 2- [6-chloro-2- (2, 4-Difluorophenylamino) -5-fluoro-nicotinoyl] -acetate. The physical values of this compound and the compound obtained in Reference Example 14 were identical.

The following compounds were obtained in the same manner as above.

Ethyl 2- [2- (2,4-difluorophenylamino) -5-fluoro-6-methoxynicotinoyl] acetate

Ethyl 2- [2- (2,4-difluorophenylamino) -6-ethylthio-5-fluoronicotinoyl] acetate ... Ethyl 2- [2- (2,4-difluorophenylamino) -5-fluoro -6-phenylthionicotinoyl] acetate

Ethyl 2- [2- (2,4-difluorophenylamino) -5-fluoro-6- (2,4,6-trimethylbenzenesulfonyloxy) nicotinoyl] acetate Ethyl 2- [6- (4-acetyl-1-piperazinyl) - 2- (2,4-Di- (3-fluorophenylamino) -5-fluoronicotinoyl] acetate.

50 ί ί 7 O 3 The physical values of these compounds and the corresponding compounds obtained in Reference Examples 13 and 14 were identical.

Reference Example 18 5 (1) 280 mg of 2- (2,4-difluorophenylamino) -5-fluoro-6-methoxynicotinic acid were suspended in 3 ml of methylene chloride, 580 mg of thionyl chloride and one drop of N, N- dimethylformamide and then the resulting mixture was allowed to react for two hours at reflux temperature. Excess solvent and thionyl chloride were removed by distillation under reduced pressure, and the crystalline material thus obtained was dissolved in 6 parts of methylene chloride.

(2) 590 mg of diphenylmethylethyl malonate was dissolved in 6 ml of anhydrous tetrahydrofuran, 90 mg of sodium hydride (50% purity) was added at 20 ° C, and then the resulting mixture was allowed to react for one hour at 0-10 ° C. The reaction mixture was then cooled to -20 ° C, the methylene chloride solution obtained in (1) above was added to the reaction mixture at a temperature of -20 to -10 ° C, and the resulting mixture was allowed to react for 30 minutes at -20 to -10 ° C. To the reaction mixture was added 120 mg of acetic acid, the solvent was removed by distillation under reduced pressure, and then 20 ml of ethyl acetate and 10 ml of water were added to the residue thus obtained. The pH of the mixture was adjusted to 2.0 with 2N hydrochloric acid. The organic layer was isolated, washed successively with 10 ml of water and 10 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Solvent removed-. . By distillation under reduced pressure, 5 ml of diisopropyl ether was added to the residue thus obtained, and the crystals were isolated by filtration to give 430 mg (yield 79.2%) of diphenylmethylethyl 2- (2,4-difluorophenylamino) -5-fluoro-6. -methoxynicotinoyl malonate, m.p. 130-3513 ° C [recrystallized from benzene-n-hexane (ti- 51 Γ :: 7 03 volume ratio 10: 1)], IR (KBr) cm -1: 1: 1 ^ ^ 1740, 1730 (shoulder), NMR ) 6 values: 1.24 (3H, t, J = 7 Hz), 3.94 (3H, s), 4.28 (2H, q, J = 7 Hz), 5.14 (1H, s), 6.40-7.64 (14 H, m), 11.10 (1H, bs).

5 (3) 200 mg of diphenylmethylethyl 2- (2,4-difluorophenylamino) -5-fluoro-6-methoxynicotinoyl malonate was dissolved in 2 ml of anisole, 2 ml of trifluoroacetic acid was added under ice-cooling, and then the resulting mixture was allowed to react for 10 minutes. at the same temperature.

The solvent was removed by distillation under reduced pressure, 2 ml of diisopropyl ether was added to the thus obtained crystalline material, and the crystals were isolated by filtration to give 120 mg (yield 94.3%) of ethyl 2- [2- (2,4-difluorophenylamino). -5-fluoro-6-metoksinikotinoyyli] acetate.

The physical values of this compound and the compound obtained in Reference Example 13 were identical.

Reference Example 19

Dissolved in 2 ml of ethyl acetate, 100 mg of ethyl 2- [2- (2,4-difluorophenylamino) -5-fluoro-6-hydroxy-20-nicotinoyl] acetate, added a diethyl ether solution containing 15 mg of diazomethane under ice-cooling, and then allowed to react the resulting mixture. 30 minutes at room temperature. So much acetic acid was then added to the reaction mixture that foaming of the reaction solution ceased. The solvent was then removed by distillation under reduced pressure, 2 ml of diisopropyl ether was added to the thus obtained crystalline material, and the crystals were isolated by filtration to give 80 mg (yield 77.0%) of ethyl 2- [2- (2,4-difluorophenylamino) -5- f-fluoro-6-methoxynicotinoyl-30 l] acetate. The physical values of this compound and the compound obtained in Reference Example 13 were identical.

Reference Example 20

Dissolved in 4 ml of methylene chloride, 400 mg of ethyl 2- [2- (2,4-difluorophenylamino) -5-fluoro-6-hydroxy-35-cotinoyl] acetate was added under ice-cooling to 52 tS; 4,6-Trimethylbenzenesulfonyl chloride and 150 mg of triethylamine and then the resulting mixture was allowed to react for two hours at room temperature. Then, 4 ml of methylene chloride 5 and 4 ml of water were added to the reaction mixture, the organic layer was isolated and 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, 2 ml of diethyl ether was added to the thus obtained crystalline material, and the crystals were isolated by filtration to give 520 mg (yield 85.8%) of ethyl 2- [2- (2,4-difluorophenylamino) -5-fluoro-6 - (2,4,6-trimethyl-benzenesulfonyloxy) nicotinoyl] acetate. The physical values of this compound and the compound obtained in Reference Example 14 were identical.

The following compounds were obtained in the same manner as above.

Ethyl 2- [2- (2,4-difluorophenylamino) -5-fluoro-6-methanesulfonyloxynicotinoyl acetate, m.p. 98-99 ° C 20 (recrystallized from benzene), IR (KBr) cm -1: V / c-0 1730, NMR (CDCl 3) δ values: 1.27 (3H, t, J = 7 Hz), δ , 28 (3H, s), 3.93 (2H, s), 4.23 (2H, q, J = 7 Hz), 6.63-7.43 (2H, m), 7.70-8, 23 (m) 1 - 25 7.97 (d, J-9 Hz) J (2H),

Ethyl 2- [2- (2,4-difluorophenylamino) -5-fluoro-6- (2,4,6-triisopropylbenzenesulfonyloxy) nicotinoyl] acetate.

The combination of this compound and that obtained in Reference Example 14. The physical values of 30 distis were identical.

Reference Example 21

Dissolved in 1.5 ml of N, N-dimethylformamide, 150 mg of ethyl 2- [6-chloro-2- (2,4-difluorophenylamino) -5-fluoronicotinoyl] acetate, added 70 mg of thiophenol 35 and 60 mg of triethylamine, and then the resulting mixture was allowed to react for one hour at room temperature. Then, 20 ml of ethyl acetate and 10 ml of water were added to the reaction mixture, and the pH of the mixture was adjusted to 2.0 with 2N hydrochloric acid. The organic layer was isolated, 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, 5 ml of n-hexane was added to the thus obtained crystalline material, and the crystals were isolated by filtration to give 10,170 mg (yield 94.6%) of ethyl 2- [2- (2,4-difluorophenylamino) -5- fluoro-6-phenylthionicotinoyl] acetate. The physical values of this compound and the compound obtained in Reference Example 14 were identical.

Reference Example 22 Dissolved in 1 ml of N, N-dimethylformamide, 100 mg of ethyl 2- [2- (2,4-difluorophenylamino) -5-fluoro-6- (2,4,6-trimethylbenzenesulfonyloxy) nicotinoyl] acetate , 17 mg of ethanethiol and 28 mg of triethylamine were added and then the resulting mixture was allowed to react for four hours at room temperature. Then, 3 ml of ethyl acetate and 3 ml of water were added to the reaction mixture, and the pH of the mixture was adjusted to 1.0 with 2N hydrochloric acid. The organic layer was isolated, 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 column chromatography [Wako Silica Gel C-200, eluent benzene-n-hexane (1: 2 by volume)] to give 50 mg (yield 67.4%) of ethyl 2 - [ 2-30 (2,4-Difluorophenylamino) -6-ethylthio-5-fluoronicotinoyl] acetate. The physical values of this compound and the compound obtained in Reference Example 14 were identical.

In the same manner as above, ethyl 2- [2- (2,4-difluorophenylamino) -5-fluoro-6-phenylthionicotino-35-yl] acetate was obtained. The physical values of this compound and the compound obtained in Reference Example 14 were identical.

54 ^ O 3

Reference Example 23

Dissolved in 58 ml of N, N-dimethylformamide, 5.80 g of ethyl 2- [2- (2,4-difluorophenylamino) -5-fluoro-6- (2,4,6-triisopropylbenzenesulfonyloxy] nicotinoyl-5] acetate, 1.24 g of thiophenol and 1.23 g of triethylamine were added, and then the resulting mixture was allowed to react for 4 hours at room temperature, then 400 ml of ethyl acetate and 200 ml of water were added to the reaction mixture, and the pH of the mixture was adjusted to 2.0 with 2N chloro-10 hydrochloric acid. The organic layer was isolated, washed successively with 200 ml of water and 200 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. 3.99 g (95.6% yield) of ethyl 2- [2- (2,4-difluorophenylamino) -5-fluoro-6-phenylthionicotinoyl] acetate were obtained, and the compound obtained in Reference Example 14 was obtained. sical values were identical.

In the same manner as above, ethyl 2- [2- (2,4-difluorophenylamino) -6-ethylthio-5-fluoronicotinoyl] acetate was obtained. The physical values of this compound and the compound obtained in Reference Example 14 were identical.

Reference Example 24 1.00 g of ethyl 2- [2- (2,4-difluorophenylamino) -5-fluoro-6-hydroxynicotinoyl] acetate was suspended in 10 ml of anhydrous acetonitrile, and 390 mg of triethylamine was added under ice-cooling. and 670 mg of diethylphosphoryl chloride, and then the resulting mixture was allowed to react for 1.5 hours at room temperature. To this reaction mixture were added 50 ml of methylene chloride and 50 ml of water, and the organic layer was isolated, 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 15 ml of n-hexane was added to the residue thus obtained, and the crystals thus precipitated were isolated by filtration to give 1.26 g (yield 91.0%) of ethyl 2- [6- diethoxyphosphinyloxy-2- (2,4-difluorophenylamino) -5-fluoronicotinoyl] acetate, m.p. 127-130 ° C. Sp. 131.5-133 ° C (recrystallized from benzene), IR (KBr) 5 cm -1 / cm -1 1740, NMR (CDCl 3) δ values: 1.30 (3H, t, J = 7 Hz), 1, 33 (3H, t, J = 7Hz), 1.35 (3H, t, J = 7Hz), 3.95 (2H, s), 4.15 (2H, q, 3 = 7Hz), 4 .25 (2H, q, J = 7 Hz), 4.30 (2H, q, J = 7 Hz), 6.65-7.35 (2H, m), 7.96 (1H, d, J = 9 Hz), 8.15-8.75 (1H, m), 11.05 (1H, bs).

In a similar manner to the above, ethyl 2- [2- (2,4-difluorophenylamino) -6-diphenoxyphosphinyloxy-5-fluoronicotinoyl acetate, m.p. 85-86 ° C (recrystallized from diethyl ether), IR (KBr) cm -1: V / c.0 1740, NMR (CDCl 3) δ values: 1.25 (3H, t, 3 = 7 Hz), 3.90 ( 2H, s), 4.20 (2H, q, 3 = 7 Hz), 6.30-7.60 (m) Ί 7.22 (bs) J (12H), 7.75-8.55 ( 2H, m), 11.07 (1H, bs).

Reference Example 25 1.40 g of ethyl 2- [2- (2,4-difluorophenylamino) -6-ethylthio-5-fluoronicotinoyl] acetate were dissolved in 14 ml of methylene chloride, added under ice-cooling. 59 g of m-chloroperbenzoic acid (purity 80%) and then the resulting mixture was allowed to react for three hours at room temperature. The precipitate was isolated by filtration, 10 ml of water was added to the filtrate thus obtained, and then the pH of the mixture was adjusted to 7.5 with saturated aqueous sodium hydrogencarbonate solution. The organic layer was isolated, 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 10 ml of diethyl ether was added to the residue thus obtained, and the crystals thus precipitated were isolated by filtration to give 1.28 g (yield 84.6%) of 35 ethyl-2- [2- (2,4-difluorophenylamino) -6- ethanesulfonyl-5-fluoronicotinoyl] acetate, m.p. 113-114.5 ° C. Sp.

56-114-115 ° C (recrystallized from diisopropyl ether), IR (KBr) cm -1: 1 / c.0 1740, NMR (CDCl 3) δ values: 1.24 (3H, t, J-7 Hz), 1.27 (3H, t, J = 7 Hz), 3.27 (2H, q, J = 7 Hz), 4.00 (2H, s), 4.18 (2H, q, J = 7 Hz) ), 6.55-7.10 (2H, m), δ 7.70-8.30 (m) δ 8.03 (d, J-9 Hz) J (2H), 10.60 (1H, bs ).

In a similar manner to the above, ethyl 2- [6-benzenesulfonyl-2- (2,4-difluorophenylamino) -5-fluoro-10-nicotinoyl acetate, m.p. 140-141 ° C (recrystallized from ethyl acetate), IR (KBr) cm -1 1740, NMR (CDCl 3) δ values: 1.27 (3H, t, J-7 Hz), 4.01 (2H, s) , 4.21 (2H, q, J-7 Hz), 6.40-7.00 (2H, m), 7.20-8.20 (m) 0 15 802 (d, J-9 Hz) J (7H), 10.72 (1 H, bs).

Reference Example 26

Dissolve 2.0 g of ethyl 2- [2- (2,4-difluorophenylamino) -5-fluoro-6-phenylthio-20-nicotinoyl] acetate in 20 ml of methylene chloride, add 1.01 g of m-chloroperbenzoic acid (purity) under ice-cooling. 80%) and then the resulting mixture was allowed to cool for five hours at the same temperature. The precipitate was then isolated by filtration, 20 ml of water was added to the filtrate thus obtained, and then the pH of the mixture was adjusted to 7.5 with saturated aqueous sodium hydrogencarbonate solution. The organic layer was isolated, 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 column chromatography [Wako Silica Gel C-200; eluent benzyl ethyl acetate 50: 1 by volume) to give 1.39 g (yield 67.1%) of ethyl 2- [6-benzenesulfinyl-2- (2,4-difluorophenylamino) -5-fluoronicotinoyl] acetate, m.p. 105-106 ° C. Sp. 107-107.5 ° C 35 (recrystallized from diisopropyl ether). IR (KBr) cm -1: 1 J C.0 1730 NMR (CDCl 3) δ values: 1.25 (3H, t, J-7 Hz), 57 li 703 3.97 (2H, s), 4, 21 (2H, q, J = 7Hz), 6.60-8.00 (8H, m), 8.30-8.85 (1H, m), 10.90 (1H, bs).

In a similar manner to the above, ethyl 2- [2,4-difluorophenylamino) -6-ethanesulfinyl-5-fluoronicotino-5-yl] acetate, m.p. 115-116 ° C (recrystallized from diisopropyl ether), IR (KBr) cm -1: δ 1735, NMR

(CDCl 3) δ values: 1.29 (3H, t, J = 7 Hz), 1.31 (3H, t, J = 7 Hz), 3.08 (2H, q, J = 7 Hz), 4 .03 (2H, s), 4.23 (2H, q, J = 7 Hz), 6.65-7.15 (2H, m), 7.97 (1H, d, J = 9 Hz), , 40-9.00 (1H, m), 10.88 (1H, bs).

Claims (3)

A process for the preparation of 1,4-dihydro-4-oxonaphthyridine derivatives of formula (I) 0 F in C00R1 Y Λν / Χ (o F where R1 is a hydrogen atom or a customary carboxyl protecting group in pyridone carboxylic acid chemistry; X is a hydrogen atom or a fluorine atom; and Y is a halogen atom; or a site thereof, characterized in that a compound is reacted with Formula 11 20 0 R 2b RH (II): IXF 30 where R 1a is a carboxyl protecting group customary in pyridone carboxylic acid chemistry; R 2b is a hydroxyl group or an optionally substituted C1-12 alkoxy, C3 alkanesulfonyl, benzenesulfonyl, C 1-4 alkanesulfonyloxy, benzenesulfonyl-oxy, di-C1-5 alkoxyphosphinyl oxy or diphenoxyphosphinyl oxy group; and X represents the salts as above; 61 ('r "· n * 7 c · l · / d 3 or a site thereof with a Vilsmeier reagent derived from an N, N-disubstituted formamide of formula III 5 R3 \? NCH (III) wherein R 3 and R 4 are the same or different and may be C 1-4 alkyl groups or together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, and from phosphoryl halide or carbonyl halide, and if necessary , removes the carboxyl protecting group or converts the product into a site. 2. Process according to claim 1, characterized in that ethyl 7-chloro-1- (2,4-difluorophenyl) -6-fluoro-4-oxo-1,8-naphthyridine-3 is prepared. carboxylic methacrylate. 20 Process according to claim 1, characterized in that ethyl 7-chloro-1- (4-fluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3 is prepared. carboxylate.