JPH0366301B2 - - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD The present invention relates to 1-substituted-6-fluoro-7-aryl(8-fluoro)-1,4-dihydro-quinol-4-one 3-carboxylic acids and their esters and cation salts. Prior Art Since the introduction of nalidimonic acid in 1963, a significant number of patents and scientific papers have been published on analogs of this compound. Representative of these publications is the following formula No. 1, issued October 14, 1969, disclosing the compound of formula
No. 3472859. The Example 7 patent discloses the antibacterial activity of compounds in which R is methyl, but no antibacterial samples are presented. Problems to be Solved by the Invention The compounds of the present invention have the formula (In the formula, R ₁ is hydrogen, alkyl having 1 to 6 carbon atoms,
benzyl or a pharmaceutically suitable cation; _R2 is hydrogen or fluoro; Y is alkyl, haloalkyl or polyhaloalkyl having 1 to 3 carbon atoms; hydroxyethyl;
Cyclopropyl; Vinyl; Allyl; Phenyl; 4
-hydroxyphenyl; or 4-fluorophenyl; R′ ₀ is hydrogen, alkylsulfinyl having 1 to 4 carbon atoms, alkylsulfonyl having 1 to 4 carbon atoms, hydroxy, alkoxy having 1 to 4 carbon atoms, Carbon number 1~
3 hydroxyalkyl, amino, carbon number 1-3
aminoalkyl, formamide, carbon number 2-3
alkanoylamino, aminosulfonyl, nitro, formyl or N-(N′,N′-dimethylformamidino); R″ ₀ is hydrogen, 3-hydroxy or 3-chloro) 1,4-dihydroquinol -4-one 3-carboxylic acid compounds. Preferred compounds are those in which R ₁ is hydrogen or a pharmaceutically suitable cation and Y is ethyl. Particularly preferred according to the invention, in which R ₂ is fluoro The compound is 6,8-difluoro-7-phenyl-1-ethyl-1,4-dihydroquinol-4-one 3-carboxylic acid 6,8-difluoro-7-(4-hydroxyphenyl)-1-ethyl- 1,4-dihydroquinol-4-one 3-carboxylic acid 6,8-difluoro-7-(4-carboxyphenyl)-1-ethyl-1,4-dihydroquinol-4-one 3-carboxylic acid 6,8- difluoro-7-(3-chloro-4-
hydroxyphenyl)-1-ethyl-1,4-dihydroquinol-4-one 3-carboxylic acid 6,8-difluoro-7-(3-hydroxyphenyl)-1-ethyl-1,4-dihydroquinol-4- 3-carboxylic acid 6,8-difluoro-7-(4-aminomethylphenyl)-1-ethyl-1,4-dihydroquinol-4-one 3-carboxylic acid 6,8-difluoro-7-(3- Aminomethylphenyl)-1-ethyl-1,4-dihydroquinol-4-one 3-carboxylic acid 6,8-difluoro-7-(4-hydroxymethylphenyl)-1-ethyl-1,4-dihydroquinol- 4-one 3-carboxylic acid 6,8-difluoro-7-(3-hydroxymethylphenyl)-1-ethyl-1,4-dihydroquinol-4-one 3-carboxylic acid 6,8-difluoro-7-( 4-Methylsulfinylphenyl)-1-ethyl-1,4-dihydroquinol-4-one 3-carboxylic acid 6,8-difluoro-7-(4-methoxyphenyl)-1-ethyl-1,4 -dihydroquinol-
4-one 3-carboxylic acid 6,8-difluoro-7-(3-methylsulfonylphenyl)-1-ethyl-1,4-dihydroquinol-4-one 3-carboxylic acid 6,8-difluoro-7-( 4-hydroxyphenyl)-1-methyl-1,4-dihydroquinol-4-one 3-carboxylic acid and 6,8-difluoro-7-(3-hydroxymethyl-4-hydroxyphenyl)-1-ethyl-
1,4-dihydroquinol-4-one 3-carboxylic acid. A particularly preferred compound in which R ₂ is hydrogen is 6-fluoro-7-phenyl-1-ethyl-
1,4-dihydroquinol-4-one 3-carboxylic acid 6-fluoro-7-(4-aminophenyl)-1
-ethyl-1,4-dihydroquinol-4-one 3
-Carboxylic acid 6-fluoro-7-(4-nitrophenyl)-1
-ethyl-1,4-dihydroquinol-4-one 3
-Carboxylic acid 6-fluoro-7-(4-formamidophenyl)-1-ethyl-1,4-dihydroquinol-4
-one 3-carboxylic acid 6-fluoro-7-(4-acetamidophenyl)-1-ethyl-1,4-dihydroquinol-4
-one 3-carboxylic acid 6-fluoro-7-(4-(N-(N',N'-dimethylformamidino))phenyl)-1-ethyl-
1,4-dihydroquinol-4-one 3-carboxylic acid 6-fluoro-7-(4-formylphenyl)-
1-ethyl-1,4-dihydroquinol-4-one 3-carboxylic acid 6-fluoro-7-(4-hydroxymethylphenyl)-1-ethyl-1,4-dihydroquinol-4-one 3-carboxylic acid 6 -Fluoro-7-(3-hydroxymethylphenyl)-1-ethyl-1,4-dihydroquinol-4-one 3-carboxylic acid 6-fluoro-7-(4-aminosulfonylphenyl)-1-ethyl- 1,4-dihydroquinol-4-one 3-carboxylic acid and 6-fluoro-7-(4-hydroxyphenyl)
-1-(4-fluorophenyl)-1,4-dihydroquinol-4-one 3-carboxylic acid. The term "polyhaloalkyl" means an alkyl having one or more halogens. Examples of polyhaloalkyl groups are dichloromethyl, dibromoethyl, perfluoropropyl. The term "halo" or "halogen" as used in the claims and description means, for example, fluoro, chloro, bromo or iodo. Means to solve the problem A compound of formula is defined above

【formula】 (hereinafter R₃(abbreviated as ) group containing a suitable aryl gold group.
Genus compounds and formulas (R in the formula₂and Y are defined above, and R¹teeth
Alkyl having 1 to 6 carbon atoms, R_FiveBromo or Yo
appropriate 7-R of_Five−Quinolinone S
Synthesized by transition metal catalyzed coupling with
It can be done. The coupling reaction is a reaction inert solvent, i.e.
Katsupurin with a reel metal compound and a compound of formula
The reaction is carried out in a solvent that does not interfere with the reaction. suitable
Reactive inert solvents include diethyl ether and zip.
Dialkyl ethers such as lopylether,
Methoxyethane and tetrahydrofuran
Ethers such as cyclic ethers such as (THF)
It is. such as to enhance the solubility of reactants.
Co-solvents can be used with ether if necessary.
Can be used. Examples of suitable co-solvents are benzene and toluene.
Aliphatic and aromatic carbons with 5 to 10 carbon atoms, such as
It is hydrogen chloride. Other suitable cosolvents are known to those skilled in the art.
Tetramethylethylenediamine (TMEDA)
and hexamethylphosphonic triamide
(HMPA). R₃Aryl metal compounds containing groups are known
can be synthesized by For example, the corresponding expression R₃R_Five(R₃
and R_Fiveis defined above)
Genide n-butyl, sec-butyl or t-
Direct lithium-halogen using butyllithium
replacement, then organometallics-in-organ
Niksynthesis (Orgnometallics in Organic
Synthesis), Volume 1, page 104 by E. Negishi.
By the known method described by (Negishi)
Synthesized by metal transfer reaction with various salts
Ru. Salts used for metal transfer are zinc, cadmium
aluminum, magnesium, mercury, tin, silver, copper, boron
and salts of aluminum, preferably
Zinc is suitable. The most commonly used salt is
Halides, especially chlorides, bromides and iodides
cyanide such as copper cyanide. most
A convenient salt is zinc chloride. The butyl lithium compound treatment described above
Suitable solvent such as single or carbon number 5-10 fat
In mixtures with aliphatic or aromatic hydrocarbons, -78~
Performed at −50°C. A suitable ether is
Dialkyl ethers such as diethyl ether
cyclic ethers such as THF and dimethoxyl.
It's Sietan. Suitable hydrocarbon solvents are e.g.
Examples are toluene and benzene. butyl lithium
The process is preferably carried out at -78°C in THF.
It's the best. The aryl metal compound is the corresponding aryl halogen.
by direct reaction of the ionide with the metal in the zero valence state.
can also be synthesized. These metals include lithium, sodium
alkali metals, such as thorium and potassium;
Alkaline earth metals such as magnesium and
It is a transition metal like lead. The reaction temperature is determined by the strength of the activity.
range from -100℃ to 100℃ for hard metals.
Ru. The solvent used in this step is ether or
or carbon in which at least one equivalent of ether is present
It is a mixed liquid with several 5 to 10 hydrocarbons. Aryl metal compounds are equivalent aryl compounds
and t-butoxide-butyllithium, TMEDA
-butyl lithium or lithium or potassium hexa
Hydrogen between strong bases like samethyldisilazane
- Can be formed by metal exchange. The aryl metal compound is a cup with the compound ()
There is generally no isolation prior to the ring reaction. Aryl metal compounds and 7-haloquinolines of the formula
Coupling with usually transition amount of 0.5~10mole%
Carry out in the presence of a metal catalyst. Transition metal catalyst is O or
is the oxidation state of
Bouchemistry (Langes Handbook of
Periodic Law as stated in Chemistry), 11th Edition
It is a metal selected from group b to group b in the table.
Contains transition metals. Suitable metals include platinum,
Cobalt, iron, zirconium, molybdenum, lute
manganese and rhodium, the more preferred
Suitable metals are palladium, platinum and nickel.
Ru. Combining transition metal catalysts with ligands to form catalysts
Match. A suitable known ligand is PPh₃,P
(CH₃)₃,P(C₂H_Five)₃,P(o-tolyl)₃,P(o-
xylyl)₃, Ph₂P(CH₂)_oPPh₂(n is an integer from 1 to 4.
number) and (CH₃)₂P(CH₂)₂,P(CH₃)₂As
phosphorus-containing ligand or cisPh₂CH＝CHPh₂,a
Cetonyl acetonate, 2,2'-bipyridylpyri
Bulletin by Jin and Tamao et al.
Of the Chemical Society of the Japan
(Bull.Chem.Soc.Japam), 49(7), 1959 (1976)
Others as described. other transition metals
The catalyst is a journal by A. Sekiya et al.
Oborganometallic chemistry (J.
Organometal.Chem.) 118, 349-354 (1976)
Accounts of
Chemical Research (Acc.Chem.Res), 15, 340~
348 (1982) and references therein.
There is. Ph is phenyl. A more suitable transition metal catalyst is (PPh₃)₂NiHal₂，
(PPh₃)_FourNi, (PPh₃)₂PdHal and (PPh₃)_FourIn Pd
Yes, Hal is chlor, bromo or iodine.
, Ph is phenyl. The most suitable catalyst is
Trakis (triphenylphosphine) palladium
It is. The reaction temperature in the coupling process is generally room temperature.
and 50℃. Methods for the synthesis of compounds of formula are described in the prior art.
It is similar to the method described above. similar to that of the prior art
The overall reaction of the two methods is shown below in reaction mechanism A and
Shown in B. In mechanism A, R₂and R_Fiveis defined above
For aniline of the formula, R′ has 1 to 6 carbon atoms.
dialkyl of the formula that is an alkyl group or benzyl
React with alkoxymethylene malonate.
The reaction is generally carried out without solvent at about 100-200°C, a suitable
The temperature is 150-175℃ for about 0.5-24 hours, the preferred temperature is 0.5
Do this for ~2 hours. Hydrocarbon intermediates of the formula that produce
like petroleum ether or diethyl ether
crystallized from an ethereal solvent, dichlorobenze
tetralin, didienyl ether or diene
Styrene glycol dimethyl ether, preferred is
Combination of commercially available diphenyl ether and dibenzofuran
Dautherm, a high-boiling solvent mixture
(Dowtherm) in high boiling point solvents like A.
Heat to 250°C to cyclize. Reaction time is about 0.5-12
It is a range of time. Let Y be the intermediate of the formula formed above as defined above.
Halide Y in which Hal is a halogen
N-substitution by -Hal. Suitable halogenation
Examples include ethyl iodide, 2-fluoro-1-
iodoethane, allyl bromide and 2-bromide
Examples include ethanol. 2-bromoethanol
For example, the adduct formed in the reaction with thionyl
Hydroxyl activation by loride followed by triethyl
Ruamine, diazabicycloundecene and dia
Elimination with a suitable base such as zabicyclononane
can be converted to a compound of the formula where Y is vinyl by
Ru. Generally substitutions are made in DMF, such as potassium carbonate.
with a suitable inorganic base at temperatures ranging from room temperature to 110°C.
Implemented. R in the formula_FiveR defined before₃to
If substituted, the reaction proceeds similarly, forming the compound
R′ in () is the water that requires the hydrolysis process the most
R defined on something other than elemental₁A compound with the formula
are synthesized. Mono- of the formula also used in the subsequent reaction of mechanism B
or di-fluoroaniline is a commercially available equivalent fluoroaniline.
from fluorobenzene to conventional nitration and reduction reactions.
It can be synthesized by reaction. In mechanism B, R₂,R_Fiveand Y are defined above
The aniline of the formula is
dial of formula 6 alkyl or benzyl
React with kylalkoxymethylene malonate
Ru. The reaction conditions are from the compound in mechanism A.
as described above with respect to the transformation of . The cyclization of formula XI formed above is similar to polyphosphoric acid
in an acidic solvent at about 100 to 250℃ for about 0.5 to 24 hours,
Suitable for heating at 100-150℃ for 0.5-2 hours.
Then, implement it. This operation is performed by Albrecht
(Albrecht), Progress Indratu by R.
Prog.Drug.Res., Volume 20, 35-49
(1977). The generated expression
This is usually done by recrystallization or chromatography.
Refined. The compound of formula is prepared by conventional methods.
can be synthesized from For example, in mechanism B, a of Eq.
Nilin with acetic anhydride in ethanol at about 25-100℃
Make it react. Hydrogenating the compound of formula formed
By reacting with a suitable base such as thorium, the Y group is
Contains halides, tosylates or mesiles
N-substitution by Compound of formulas formed
Aqueous solvents such as 6N hydrochloric acid remove acetyl groups from substances.
When removed by refluxing in
is formed. The N-substituted aniline of formula
Diborane, palladium/carbon and hydrogen, hydrogenated hydrogen
Sodium or cyanoborohydride
For reductive amination with a suitable reducing agent such as
Therefore, a suitable acid anhydride of the aforementioned aniline of the formula
Acylation and reaction with hydrates or acid chlorides
Direct reduction of aniline and aniline X with diborane in THF
It can also be formed by N-substitution of the initial formula in mechanism B is mechanism A
From the late N-substitution of compounds of formula
Substitution with polyfluoroalkyl halide
is not a viable route, so Y
Particularly useful in the case of loalkyls. R₃is alkylsulfinyl or alkylsulfinyl
A compound of the formula that is sulfonyl-substituted phenyl is R₃
is phenylmercaptoalkyl
obtained by conventional oxidation of the compound. R₃is hydro
Compounds that are xyphenyl are R₃is methoxyfue
The corresponding compound is boron tribromide or
Ether cleavage such as trimethylsilyl iodide
can be formed by reaction with agents. R₃is hydroxymethylphenyl
() is R₃is trialkylsilyloxymethylphene
(each alkyl has 1 to 4 carbon atoms)
Reaction of the corresponding compound with the ether cleavage agent described above
can be synthesized more conveniently. R₃is nitrophenyl
The compound () is R₃is phenyl
It can be synthesized by conventional nitration of compound (). child
The reduction of nitrophenyl compounds is R₃is aminof
Gives a compound that is enyl. Alkyl halogen
alkyl by common alkylating agents such as
This aminophenyl compound becomes R₃is al
Kylaminophenyl or dialkylaminophenyl
produces a compound () which is nil. Similarly,
R₃is alkylaminoalkylphenyl and di
The compound () which is alkylaminophenyl is
R₃is aminoalkylphenyl
Synthesized by alkylation of compounds. R₃is N,N-dimethylformamidophenyl
The compound () is R₃is aminophenyl
Formic acid or formic acid derivatives such as ethyl formate
Formed by reaction with a conductor. R₃is arcano
A compound () that is ylamino is R₃is aminof
Acid chloride or no acid chloride of the corresponding compound that is enyl
Acid anhydrides, such as acetic acid, contain alkanoyl groups.
Can be synthesized using reagents. R₃is formamidinophenyl
() is R₃Compounds where is aminophenyl ()
Dimethylformamide dimethylacetate in toluene
It can be formed by reacting with tar. Aminosulfonyl-substituted phenyl compounds are R₃but
of the compound () which is chlorosulfonylphenyl
Amino group introduction agents such as ammonia or amines
It can be obtained as a result of a drug-induced reaction. Chlorosulfonyl
The base is R₃Chlorosulfonate of compounds where is phenyl
introduced by reaction with phosphoric acid. aminosulfony
Alkylation of ruphenyl compounds is R₃is alkyl
Aminosulfonyl or dialkylaminosulfonyl
It produces a compound () which is nylphenyl. Ma
These latter compounds each have R₃is Chloros
Monoalkaline of compound () which is sulfonylphenyl
From reaction with kylamine or dialkylamine
can be obtained. R₃The compound () in which is formyl phenyl is
R₃is hydroxymethylphenyl
Compounds such as DMSO and triethylamine
By oxidation, such as that with quizaryl chloride.
Can be synthesized. R₁The compound () in which is hydrogen is R₁is alkyl
or the corresponding ester acid or benzyl
by base hydrolysis or R₁is benzyl a
obtained by hydrogenolysis of the corresponding compound. The compound of formula
It has antibacterial properties in the addition salt form. Pharmaceutically suitable cationic salts of compounds of formula are
Can be synthesized by conventional methods. For example, R₁but
Compounds with the formula hydrogen are suitable as medicines for the purpose
treated with an aqueous solution of positive cations, and distilled the resulting solution.
by drying (preferably under reduced pressure).
salts can be synthesized. A suitable drug for this purpose
Suitable cationic salts include potassium and sodium.
alkali metal salts such as lithium salts, calcium
Alkaline earth metals such as magnesium salts
salt, and ammonia, choline, and diethanolamine.
Examples include organic amine salts such as amines. Although the compounds of the invention can be administered alone,
generally related to the intended route of administration and standard formulation practices.
Administered as a mixture with a pharmaceutical carrier selected as
be done. excipients such as starch or lactose
Containing tablet form or alone or in combination with excipients
capsules or elixirs containing flavorings or colorings
It can be administered orally in the form of a pill or suspension. animal
Concentrations of 10 to 1000 ppm in feed and drinking water
(preferably 10 to 300 ppm)
Ru. Parenterally, e.g. intramuscularly, intravenously or subcutaneously.
Injections can also be given. For parenteral administration, make an isotonic solution.
Contains enough salt and other solutes like glucose to
It is most commonly used in the form of a sterile aqueous solution. general
The compound () is a buffer, preservative, and isotonic saline solution.
or substances known to those skilled in the art for making isotonic solutions such as
dissolved in a pharmaceutically suitable liquid, such as water, which may contain
be done. The reconstituted solution prepared in this way can be directly
Can be used for parenteral injection or by mixing
added to solutions such as intravenous solutions for delayed administration.
can be added. The present invention provides that an antimicrobially effective amount of the compound of formula () is
Formulated with pharmaceutically suitable diluents or carriers
The present invention also provides agent compositions. The compounds of the invention may be used orally for the treatment of bacterial diseases.
It can be administered to humans either parenterally or parenterally. Orally
Approximately 0.1-500mg/Kg/day, preferably 0.5-500mg/Kg/day.
Administered parenterally at a dose of 200 mg/Kg/day.
Generally speaking, approximately 50 to 500 doses can be administered in one go or in three divided doses.
It can be administered in a dosage of mg/Kg/day. To those skilled in the art
As is known, the weight and condition of the patient undergoing treatment
Variations may be inevitable depending on the condition or route of administration selected.
can occur. The antibacterial activity of the compounds of the invention was demonstrated by E. Steers.
(Steers) et al.
Antibiotics and Chemotherapy,
9, 307 (1959).
The test follows the Stayers copying technique.
More shown. Example 1 A 3-bromo-2,4-difluoronitroben
Zen 10ml concentrated HNO₃and 10ml H₂S.O._Fourmixture of 50
30 g of 2,6-difluoro dissolved in ml of concentrated sulfuric acid
It was added dropwise to a stirred solution of bromobenzene under cooling. Mixed
Adjust the dropping rate so that the temperature of the mixture does not rise above 55℃.
Adjusted. After the addition was completed, the reaction mixture was kept at room temperature for 2 hours.
Stir for a while. Next, I poured this over ice and it was done.
The solid matter was filtered and washed with water. Dry this and
A yellow solid was obtained. m.p.50−51.5℃, yield 84%
(31.2g). Elemental analysis: C₆H₂BrF₂NO.₂as Calculated value: C, 30.28; H, 0.85; Br, 33.57; F,
15.96; N, 5.89% Actual value: C, 30.34; H, 0.98; Br, 33.81; F,
16.04; N, 5.81% B 3-amino-2,6-difluorobromoben
Zen 31.2g 3-bromo-2,4-difluoronite
Lobenzene, 150 ml concentrated HCl and 150 g dichloride
Preheat the tin dihydrate mixture to 60°C.
Place in the oil bath. Then a small amount of diethyl ethyl
ether was added to make a solution. Heat at 60℃ for 30 minutes
After that, cool the mixture and pour it into 1500ml of ice water.
Ta. Next, use 30% sodium hydroxide water to adjust the pH to 13.
Ta. During this time, it was cooled externally and kept below 25°C. Mixed
The compound was extracted three times with chloroform and the combined organic
The extract was washed with water. The organic layer was dried and evaporated,
A white solid was obtained. m.p.77-78℃, yield 90.5%
(24.7g) C ethyl 7-bromo-6,8-difluoro-
4-Hydroxyquinoline-3-carboxylate
to 26 g of 3-amino-2,6-difluorobromo
Benzene and 27g diethyl ethoxymethylene
The stirred mixture of ronate was heated at 150° C. for 1 hour.
After cooling, 100 Dowtherm “A”
(High boiling points of diphenyl ether and dibenzofuran)
Add a point inert solvent (commercially available) and heat for 260 min under nitrogen gas.
Heated at ℃ for 1.5 hours. After cooling the mixture to room temperature,
Added 200ml hexane. Take the formed precipitate,
Washed with hexane. Dry this to a creamy consistency.
I got a shape. m.p. 285°C, yield 78% (32.32 g). D ethyl 7-bromo-6,8-difluoro-
1-ethyl-1,4-dihydroquinol-4-
On 3-carboxylate 32 in 450 ml of N,N-dimethylformamide
g of ethyl 7-bromo-6,8-difluoro-
4-hydroxyquinoline-3-carboxyle
45.1 g of iodomethane and 50 g of anhydrous carbonate
Heat the lucium mixture at 90°C for 2 hours with stirring.
Ta. The mixture was then cooled and poured into water. Out
The resulting precipitate was filtered off and dried. The crude product,
Ethyl acetate/hexane (60:
40) and purified with , white crystals were isolated.
m.p. 153-155°C, yield 86% (29.84 g). Elemental analysis: C₁₄H₁₂BrF₂NO.₃as Calculated value: C, 46.66; H, 3.33; N, 3.88% Actual value: C, 46.38; H, 3.37; N, 3.87% E ethyl 6,8-difluoro-1-ethyl-7
-Phenyl-1,4-dihydroquinol-4-
One 3-carboxylate (R₁= ethyl, R₂
=F,R₃= phenyl, Y = ethyl) 60/30, cyclohexane/diethyl ether mixture
10 ml of 2.7M phenyllithium solution in liquid
ml of dry tetrahydrofuran. blend
Stir at room temperature under nitrogen gas and add 10 ml of tetrahydride.
A solution of 409 mg anhydrous zinc chloride in Lofuran was added.
After 20 minutes, dissolved in 10 ml of tetrahydrofuran.
360 mg ethyl 7-bromo-6,8-difluoro
-1-ethyl-1,4-dihydroquinol-4-
on 3-carboxylate and 124mg palladium
Solution of mutetrakis (tri-phenylphosphine)
liquid was added. Heat the mixture at 40-45°C for 18 hours.
Ta. Then cool the mixture and pour into 200ml of water.
Ta. After stirring the mixture for 20 minutes, it was extracted three times with chloroform.
The organic extracts were combined. Wash with water, dry and store
The crude product was obtained. Using a silica column,
Elute the product with ethyl acetate to remove the pure product as a solid.
and isolated. (251 mg, 70% yield) NMR (CDCl)₃, 60MHz): 8.4 (s, 1H), 8.1 (dd,
1H, J = 9Hz and 2Hz), 7.5 (s, 5H), 4.4
(m, 4H), 1.5 (t, 3H, J=6.5Hz), 1.4 (t,
3H, 6.5Hz) MS:C₂₀H₁₇F₂NO.₃As, calculated value: 357.1178;
Actual value: 357.1164 F 6,8-difluoro-1-ethyl-7-phene
Nyl-1,4-dihydroquinol-4-one 3
-carboxylic acid (R₁=H;R₂=F;R₃= phenyl; Y = ethyl
) Add ethyl 6,
8-difluoro-1-ethyl-7-phenyl-
1,4-dihydroquinol-4-one 3-carbo
Dissolve the xylate (186 mg) and leave the mixture for 3.5 hours.
The mixture was heated to reflux. Cool the mixture and remove the resulting precipitate.
I took it. A solid product was obtained by washing with water and drying. m.p.＞260℃ (114mg, 66% yield) NMR (DMSO−d₆, 250MHz): 8.75 (s, 1H),
7.9 (dd, 1H, J=9Hzand2Hz), 7.35 (s, 5H),
4.5 (m, 2H), 1.35 (t, 3H, J=6Hz) MS:C₁₈H₁₃F₂NO.₃Calculated value: 329.0864, real
Measured value: 329.0860 Elemental analysis: C₁₈H₁₃F₂NO.₃as Calculated value: C, 63.34; H, 4.00; N, 4.10% Actual value: C, 63.08; H, 4.02; N, 4.14% Example 2 Ethyl 6,8-difluoro-1-ethyl-7-
(4-ethylthiophenyl)-1,4-dihydro
Quinol-4-one 3-carboxylate
(R₁= ethyl; R₂=F;R₃=4-methylthiof
enyl; Y=ethyl) 2M solution of t-butyllithium in pentane
Dissolve 12.5ml in 35ml dry tetrahydrofuran.
Stirring of 2.53 g of 4-bromo-thioanisole
It was added dropwise into the solution at −78° C. under nitrogen gas. −78℃
After stirring for 1 hour, dissolve in 25 ml of tetrahydrofuran.
Add 1.7g of clarified anhydrous zinc chloride solution and mix.
The mixture was stirred for an additional 15 minutes at -78°C. 620mg in solution
palladium tetrakis (triphenylphosphide)
) and then into 10 ml of tetrahydrofuran.
1.8 g of ethyl 7-bromo-6,8-di dissolved
Fluoro-1-ethyl-1,4-dihydroquino
Dissolve the solution of lu-4-one 3-carboxylate.
I added it. After addition, the mixture was kept at −78°C for an additional 15 minutes.
Stir for a while. Warm to room temperature, 24 hours later, 5%
5 ml of aqueous ammonia chloride was added. Next, 1M hydrochloric acid 5
ml was added and the mixture was stirred for 10 minutes. 200ml water
Pour into the solution and extract three times with 50 ml of chloroform each time.
The machine extracts were combined. Wash once with water, dry and evaporate
The crude product was obtained as a yellow solid. silica
This was purified by eluting with ethyl acetate.
The desired product was isolated. (1.7g, yield 55%) NMR (CDCl)₃, 60MHz): 8.35 (s, 1H), 8.05
(dd, 1H, J=9Hzand2Hz), 7.35 (m, 4H),
4.35 (2q, 4H, J=6.5Hz), 2.6 (s, 3H), 1.5
(t, 3H, J=6.5Hz), 1.4(t, 3H, J=6.5
Hz) MS:C_{twenty one}H₁₅NO.₃Calculated value as S: 403.1054; Actual
Measured value: 403.1031 Example 3 A Ethyl 6,8-difluoro-1-ethyl-7
-(4-methylsulfinylphenyl)-1,4
-dihydroquinol-4-one 3-carboxylic acid
(R₁= ethyl; R₂=F,R₃=4-methylsulf
Inylphenyl; Y=ethyl) 101mg 85% dissolved in 3ml dichloromethane
A solution of m-chloroperbenzoic acid was added to dichloromethane.
201 mg of ethyl 6,8-difluoro-
1-Ethyl-7-(4-methylthiophenyl)-
1,4-dihydroquinol-4-one 3-carbo
A solution of xylate was added dropwise at room temperature. After 1.5 hours,
The reaction mixture was diluted with 10 ml of 5% sodium bicarbonate.
It was washed twice and the organic phase was dried. Distill this and coarsely
The product was obtained as an oil. silica gel column
first with ethyl acetate, then with ethyl acetate.
This was purified by gradient elution with 100 ml/methanol.
Ta. The product was a hard glass. (90 mg, yield
43%) NMR (CDCl)₃, 60MHz): 8.4 (s, 1H), 8.1 (dd,
1H, J=9Hz and 2Hz), 7.7 (m, 4H), 4.4
(2q, 4H, J=6,5Hz), 2.8 (s, 3H), 1.5
(t, 3H, J=6.5Hz), 1.4(t, 3H, J=6.5
Hz) B 6,8-difluoro-1-ethyl-7-(4
-methylsulfinylphenyl)-1,4-di
Hydroquinol-4-one 3-carboxylic acid
(R₁=H;R₂=F;R₃=4-methylsulfini
Ruphenyl; Y = ethyl) By the method of Example 1F, 90 mg of ethyl 6,8
-difluoro-1-ethyl-7-(4-methyls)
(rufinylphenyl)-1,4-dihydroquino
Notation generated from lu-4-one 3-carboxylate
I got something. 60 mg (72% yield). White solid m.p.260
℃ NMR (DMSO d₆, 250MHz); 9.07 (s, 1H),
8.1 (dd, 1H, J = 9Hz and 2Hz), 7.87 (m,
4H), 4.65 (m, 2H), 2.85 (s, 3H), 1.5 (t,
3H, J=6Hz) MS:C₁₉H₁₅F₂NO._FourAs S, calculated value: 391.0.690 Actual value: 391.0621 Elemental analysis: C₁₉H₁₅F₂NO._Fouras S Calculated value: C, 58.31; H, 3.83; N, 3.58% Actual value: C, 57.89; H, 4.15; N, 3.36% Example 4 A 4-fluoro-3-phenylnitrobenzene 2-Fluoro-5-nitroaniline (30g)
of 60 ml of nitrite dissolved in 225 ml of benzene.
Add to the mill's refluxing solution in portions over 45 minutes.
Ta. After heating to reflux for an additional 30 min, the mixture was cooled and the solvent
was distilled off under vacuum. How many times should the residue be heated with petroleum ether?
It was crushed and the extracts were combined. This is distilled off to produce the product
was obtained as a red oil (19.9 g, yield 49%).
This material was used without further purification. NMR (CDCl)₃, 60MHz); 8.0-8.4 (m, 3H), 7.1
-7.6 (m, 5H) B 4-fluoro-3-phenylaniline 18.5 g of 4-fluoro-3-phenylnitrobe
76.7 g of stannous chloride dihydrate and 150
ml of concentrated hydrochloric acid was heated at 60° C. for 2 hours with stirring. cold
After cooling, dissolve the formed precipitate in water and dilute the mixture with sodium carbonate.
Made basic with thorium. Chloroform the mixture
The organic extracts were extracted five times and the organic extracts were combined. dry,
Evaporation gave the product as a light brown oil (10.9
g, yield 68%), which was used without further purification. NMR (CDCl)₃, 60MHz): 7.15 (m, 5H), 7.1−
6.1 (m, 3H), 3.3 (br.s, 2H) C diethyl 4-fluoro-3-phenylanili
Nomethylene malonate 10.9g 4-fluoro-3-phenylaniline
and 12.54g diethyl ethoxymethylene marone
The mixture was heated at 150°C for 15 minutes. blend
Cool and triturate with petroleum ether to obtain a solid product.
(16.73 g, 80% yield). Refine this further
I used it all the time. NMR (CDCl)₃, 60MHz): 8.3 (d, 1H, J=14
Hz), 7.5-6.9 (m, 8H), 4.2 (m, 4H), 1.4
(m, 6H) D Ethyl 6-fluoro-7-phenylquinoline
-4-ol 3-carboxylate 16.73g dissolved in 100ml Dowtherm “A”
Diethyl 4-fluoro-3-phenylanilinome
The solution of tyrene malonate was heated to 250 °C for 2.5 h under stirring.
Heated. Cool the mixture and remove the formed precipitate.
Ta. Washed with petroleum ether and dried. m.p.＞270
°C (12.37 g, 85% yield). NMR (trifluoroacetic acid-d, 60MHz): 9.3
(s, 1H), 8.2 (m, 2H), 7.5 (m, 5H), 4.7
(q, 2H, J = 6.5Hz), 1.5 (t, 3H, J = 6.5
Hz). E ethyl 1-ethyl-6-fluoro-7-phene
Nyl-1,4-dihydroquinol-4-one 3
-carboxylate (R₁= ethyl; R₂=H;
R₃= phenyl; Y = ethyl) 12.4 g of ethyl 6-fluoro-7-phenyl
Norin-4-ol 3-carboxylate, 11g
of anhydrous sodium carbonate and 18.7 g of iodometh
Mixture: 100ml of N,N-dimethylformamide
The mixture was heated at 80°C for 4 hours. Cool the reaction mixture
and poured into ethyl acetate. water the mixture several times
Washed and dried the organic phase. This is distilled off to remove the solid matter.
Obtained. Wash thoroughly with diethyl ether and dry.
A white solid was obtained. (9.16g, 68% yield) NMR (CDCl)₃, 60MHz): 8.4 (s, 1H), 8.05 (d,
1H, J = 10Hz), 7.5 (m, 6H), 4.3 (q, 2H,
J = 6.5Hz), 4.25 (q, 2H, J = 6.5Hz), 1.55
(t, 3H, J=6.5Hz), 1.35 (t, 3H, J=6.5
Hz) F 1-ethyl-6-fluoro-7-phenyl-
1,4-dihydroquinol-4-one 3-cal
Bonic acid (R₁=R₂=H;R₃= Phenyl; Y = E
Chill) 0.44g ethyl 1-ethyl-6-fluoro-7
-phenyl-1,4-dihydroquinol-4-o
3-carboxylate, 10 ml of 1M sodium hydroxide
The mixture of aluminum and water was stirred at 90°C for 1 hour. mixture
Cool the thing and pour it into 20 ml of water. with 1M hydrochloric acid
The temperature was adjusted to Hz7, and the resulting precipitate was collected. water this
Washed, washed with ether and dried, white solid
I got it. m.p.253-256℃ (0.26g, 65% yield) NMR (trifluoroacetic acid-d, 60MHz): 9.4
(s, 1H), 8.3 (m, 2H), 7.6 (m, 5H), 4.9
(q, 2H, J = 6.5Hz), 1.8 (t, 3H, J = 6.5
Hz). Elemental analysis: C₁₈H₁₄FNO₃・1.5H₂As O; Calculated value: C, 63.90; H, 5.02; N.4.14% Actual value: C, 63.52; H, 4.66; N, 3.92% Example 5 A Ethyl 1-ethyl-6-fluoro-7-(4
-nitrophenyl)-1,4-dihydroquino
Lu-4-one 3-carboxylate (R₁=E
Chill;R₂=H;R₃=4-nitrophenyl; Y
= ethyl) Ethyl 1-ethyl-6-fluoro-7-phenylene
Ru-1,4-dihydroquinol-4-one 3-ka
Ruboxylate (4g) in 12ml concentrated sulfuric acid and 12ml
was added little by little to a mixture of concentrated nitric acid at 0° C. while stirring.
After 1 hour at 0°C, the mixture was poured onto ice. Out
Collect the resulting precipitate and wash the solid with ethyl acetate.
Ta. Next, both crystals were crystallized with hot ethyl acetate to obtain a solid.
m.p.210-212℃ (2.88g, 68% yield) NMR (trifluoroacetic acid-d, 25MHz): 9.5
(s, 1H), 8.5 (m, 4H), 8.0 (m, 2H), 5.05
(q, 2H, J = 6.5Hz), 4.75 (q, 2H, J = 6.5
Hz), 1.85 (t, 3H, J = 6.5Hz), 1.5 (t, 3H,
J=6.5Hz) MS: 384 (parent ion peak), 312 (reference peak) B 1-ethyl-6-fluoro-7-(4-nito
Lofenyl)-1,4-dihydroquinol-4
-one 3-carboxylic acid (R₁=H;R₂,R₃as well as
Y is the same as Example 5A) 0.65g ethyl 1-ethyl-6-fluoro-7
-(4-nitrophenyl)-1,4-dihydroquino
ru-4-one 3-carboxylate and 15 ml of
1M sodium hydroxide water mixture under stirring for 30 minutes
Heated to 90°C. Cool the mixture then add 40ml water
poured into. Adjust the pH of the mixture to 7 with 1M hydrochloric acid,
The resulting precipitate was collected. Rinse the solids with water and
and ethyl acetate. Next, heat N, N
-Recrystallize from dimethylformamide to obtain a white solid.
Obtained. m.p.＞270℃ (0.29g, 48% yield) NMR (trifluoroacetic acid-d, 60MHz): 9.5
(s, 1H), 8.5−7.7 (m, 6H), 5.1 (q, 2H),
1.85 (t, 3H) Example 6 A Ethyl 1-ethyl-6-fluoro-7-(4
-aminophenyl)-1,4-dihydroquino
Lu-4-one 3-carboxylate (R₁=Y
= ethyl; R₂=H;R₃=4-aminophenyl) 1.7 g of ethyl 6-fluoro-7-(4-nitro
phenyl)-1,4-dihydroquinol-4-o
3-carboxylate, 12.75 g stannous chloride
A mixture of dihydrate and 13 ml of concentrated hydrochloric acid was heated at 0°C for 15 min.
The mixture was stirred for 1 minute and then at room temperature for 2 hours. mixture
It was cooled and the resulting precipitate was collected. Dissolve this in water
The solution was adjusted to Hz9 with solid sodium bicarbonate.
Ta. several times with ethyl acetate, then several times with chloroform.
Extracted. The combined extracts are washed with water, dried and distilled off.
A white solid was obtained. m.p.248-250℃ (1.25g,
78% yield). NMR (DMSO−d₆, 250MHz); 8.7 (s, 1H),
7.9 (d, 1H, J = 11.5Hz), 7.75 (d, 1H, J
= 6Hz), 7.4 (dd, 2H, J = 9Hz), 6.7 (d,
2H, J = 9Hz), 4.5 (q, 2H, J = 6.5Hz),
4.25 (q, 2H, J = 6.5Hz), 1.45 (t, 3H, J
= 6.5Hz), 1.3 (t, 3H, J = 6.5Hz) B 1-ethyl-6-fluoro-7-(4-amino)
nophenyl)-1,4-dihydroquinol-4
-one 3-carboxylic acid (R₁=R₂=H;R₃=4
-aminophenyl; Y: ethyl) 0.8g ethyl 1-ethyl-6-fluoro-7
-(4-aminophenyl)-1,4-dihydroquino
ru-4-one 3-carboxylate and 16 ml of
The mixture of 2M hydrochloric acid was heated to reflux for 6 hours. blend
The precipitate formed by cooling is washed with water and dried to obtain the product.
was obtained as a yellow solid. m.p.270−272℃ (0.59
g, 78% yield) NMR (trifluoroacetic acid-d, 250MHz): 9.55
(s, 1H), 8.6 (d, 1H, J=8.5Hz), 8.45
(d, 1H, J=6Hz), 8.0 (d, 2H, J=9.5
Hz), 7.85 (d, 2H, J=9.5Hz), 5.1 (m,
2H), 1.9(t, 3H) MS: 326 (parent ion peak), 282 (reference peak) Elemental analysis: C₁₈H₁₅FN₂O₂as Calculated value: C, 58.22; H, 5.39; N, 7.54% Actual value: C, 58.25; H, 4.73; N, 7.44% Example 7 1-ethyl-6-fluoro-7-(4-form
amidophenyl)-1,4-dihydroquinol
-4-one 3-carboxylic acid (R₁=R₂=H;R₃
=4-formamidophenyl; Y=ethyl) 1-ethyl-6-fluoro-7-(4-amino
phenyl)-1,4-dihydroquinol-4-o
Mix 3-carboxylic acid (100 mg) with 1 ml of formic acid.
The mixture was heated under reflux for 5 hours. Cool the mixture and remove the solvent.
Distilled under vacuum. Mix the resulting solid with water and diethyl
Dry with ether to give the product as a pale yellow solid.
Obtained. m.p.＞270℃ (86mg, 79% yield) NMR (DMSO−d₆/trifluoroacetic acid-d,
250MHz): 9.4 (s, 1H), 8.5 (s, 0.5H), 8.4
(d, 1H, J=9Hz), 8.3(d, 1H, J=6
Hz), 8.2 (s, 0.5H), 7.9 (d, 2H, J=8
Hz), 7.8 (d, 2H, 8Hz), 5.0 (q, 2H, J=
6.5Hz), 1.75 (t, 3H, 6.5Hz) Elemental analysis: C₁₉H₁₅FN₂O_Four・1.5H₂as O Calculated value: C, 59.84; H, 4.72; N, 7.35% Actual value: C, 60.24; H, 4.31; N, 7.08% Example 8 1-ethyl-6-fluoro-7-(4-aceto
amidophenyl)-1,4-dihydroquinol
-4-one 3-carboxylic acid (R₁=R₂=H;R₃
=4-acetamidophenyl; Y=ethyl) 1 in a mixture of 1 ml acetic acid and 0.5 ml acetic anhydride.
-ethyl-6-fluoro-7-(4-aminophe
Nyl)-1,4-dihydroquinol-4-one 3
- Add carboxylic acid (50 mg) and leave at room temperature for 1.5 hours.
It was stirred with Take the formed precipitate and add water and ether.
Wash the product with m.p. > 250°C as a white solid.
(35 mg, 62% yield) NMR (trifluoroacetic acid-d, 250MHz): 9.5
(s, 1H), 8.55 (d, 1H, J=9Hz), 8.4 (d,
1H, 6Hz), 7.85 (d, 2H, J=6Hz), 7.75
(d, 2H, 6Hz), 5.05 (m, 2H), 2.55 (s,
3H), 1.85 (t, 3H, J=6Hz) Example 9 1-ethyl-6-fluoro-7-(N-(N',
N'-dimethylformamidino-phenyl)-
1,4-dihydroquinol-4-one 3-cal
Bonic acid (R₁=R₂=H;R₃=N-(N', N'-di
methylformamidinophenyl); Y=ethyl) 1-ethyl-6-fluoro-7 in toluene
-(4-aminophenyl)-1,4-dihydroquino
ol-4-one 3-carboxylic acid (100 mg) and N,
N-dimethylformamide dimethyl acetal
(74 mg) was heated under reflux for 3 hours. 38 more
mg of N,N-dimethylformamide dimethyl-a
Setal was added and the mixture was heated under reflux for 2 hours. Cool the mixture
The solid substance obtained by evaporating the solvent in vacuo is converted into ether.
Washed and dried. Product as pale yellow solid
Obtained. m.p. 215-218°C (70 mg, 57% yield). NMR (DMSO−d₆/trifluoroacetic acid-d,
250MHz): 9.2 (s, 1H), 8.5 (s, 1H), 8.3
(d, 1H, J=9Hz), 8.15 (d, 1H, J=6
Hz), 7.85 (d, 2H, J=6Hz), 7.6 (d, 2H,
J = 6Hz), 4.8 (m, 2H), 3.45 (d, 6H, J =
18Hz), 1.65 (t, 3H, J=6Hz) MS: 381 (66%) Elemental analysis: C_{twenty one}H₂₀FN₃O₃as Calculated value: C, 63.16; H, 5.51; N, 10.52% Actual value: C, 62.94; H, 5, 25; N, 9.94% Example 10 A Ethyl 1-ethyl-6-fluoro-7-(4
-chlorosulfonylphenyl)-1,4-dihy
Droquinol-4-one 3-carboxylate Ethyl 1- dissolved in dichloromethane (20ml)
Ethyl-6-fluoro-7-phenyl-1,4-
Dihydroquinol-4-one 3-carboxylate
Add chlorosulfonic acid (10ml) to a solution of (2.5g)
was added over 15 minutes at 0° C. with stirring. mixture
Stir the mixture at 0°C for an additional 15 min, then at room temperature for 1.5 h.
did. Pour the mixture into ice water and dilute with ethyl acetate.
Extracted twice. Dry and evaporate the combined organic extracts.
The product was obtained as an oily solid. (1.4g, 42
%yield). This was used immediately without further purification. NMR (CDCl)₃, 60MHz): 8.6 (s, 1H), 8.4−7.4
(m, 6H), 4.4 (2q, 4H, J=6.5Hz), 1.6 (t,
3H, J = 6.5Hz), 1.4 (t, 3H, J = 6.5Hz) B Ethyl 1-ethyl-6-fluoro-7-(A
Minosulfonylphenyl)-1,4-dihydro
Quinol-4-one 3-carboxylate
(R₁= ethyl; R₂=H;R₃=4-aminosulfo
Nylphenyl; Y=ethyl) Ethyl 1-ethyl dissolved in 8 ml dichloromethane
Chyl-6-fluoro-7-(4-chlorosulfony)
(ruphenyl)-1,4-dihydroquinol-4-
In a solution of On 3-carboxylate (0.7 g),
Add ammonia saturated ethanol solution (1 ml) under stirring.
Added at −50°C. Allow the mixture to slowly warm to room temperature.
Warm up. After 2 hours, pour the mixture into water and drain it.
Take the resulting precipitate and mix with water, ethyl acetate, and ether.
Each was washed. Dry this and the product turns white
Obtained as a solid. (0.4g, 60% yield) NMR (DMSO−d₆, 60MHz): 8.7 (s, 1H),
8.2−7.4 (m, 6H), 4.5 (q, 2H, J=6.5Hz),
4.3 (q, 2H, J = 6.5Hz), 1.5 (t, 3H, J =
6.5Hz), 1.4 (t, 3H, J = 6.5Hz) C 1-ethyl-6-fluoro-7-(4-amino)
(nosulfonylphenyl)-1,4-dihydroxy
Nor-4-one 3-carboxylic acid (R₁=
H;R₂,R₃and Y are the same as Example 10B) 0.4g ethyl 1-ethyl-6-fluoro-7
-(4-aminosulfonylphenyl)-1,4-di
Hydroquinol-4-one 3-carboxylate
5 ml of ethanol, 5 ml of 1M sodium hydroxide
The water mixture was heated at 90°C for 30 minutes. mixture
Cooled and concentrated under vacuum. PH7 using 1M hydrochloric acid
I made it. The resulting precipitate was collected and washed. Dry this
Drying gave the product as a white solid. m.p.＞
270℃ (0.3g, 78% yield) NMR (DMSO−d₆/trifluoroacetic acid-d,
250MHz): 9.45 (s, 1H), 8.5 (d, 1H, J=
9Hz), 8.4 (d, 1H, J = 6Hz), 8.2 (d, 2H,
J = 6.5Hz), 7.95 (d, 2H, J = 6.5Hz), 5.0
(q, 2H), 1.8 (t, 3H, J = 6.5Hz) Elemental analysis: C₁₈H₁₅FN₂O_FiveS・0.5H₂as O Calculated value: C, 54.10; H, 4.01; N, 7.01% Actual value: C, 53.59; H, 4.00; N, 6.71% Example 11 A Ethyl 6,8-difluoro-7(3-methoxy)
Cyphenyl)-1-ethyl-1,4-dihydro
Quinol-4-one 3-carboxylate Following the method of Example 2, 935 mg of 1-bromo-
3-methoxybenzene, 5 ml 2M t-butyl lithium
solution, 818 mg anhydrous zinc chloride, 720 mg ethyl
7-bromo-6,8-difluoro-1-ethyl-
1,4-dihydroquinol-4-one 3-carbo
xylate and 248 mg of tetrakis-(triphenylene)
471 mg (60%
yield) of the product was obtained. NMR (CDCl)₃, 60MHz): 8.4 (s, 1H), 8.1 (dd,
1H, J=9 and 2Hz), 7.6-6.9 (m, 4H),
4.4 (2q, 4H, J=6.5Hz), 3,8 (s, 3H),
1.5 (t, 3H, J = 6.5Hz), 1.4 (t, 3H, J =
6.5Hz) MS: Calculated value: C_{twenty one}H₁₉F₂NO._Fouras: 387.1285 Actual value: 387.1267 B 6,8-difluoro-7-(3-methoxyf
enyl)-1-ethyl-1,4-dihydroquino
R-4-one 3-carboxylic acid Following the method of Example 1F, 471 mg of ethyl 6,8
-difluoro-7-(3-methoxyphenyl)-1
-ethyl-1,4-dihydroquinol-4-one
327 mg (76%) using 3-carboxylate
The product was obtained as a white solid. m.p.＞260℃ NMR (DMSO−d₆, 250MHz): 9.05 (s, 1H),
8.05 (dd, 1H, J = 9Hz and 2Hz), 7.5 (t,
1H), 7.15 (m, 2H), 4.65 (m, 2H), 3.85 (s,
3H), 1.45 (t, 3H, J=6Hz) MS:C₁₉H₁₅F₂NO._FourAs, Calculated value: 359.0963 Actual value: 359.0979 Elemental analysis: C₁₉H₁₅F₂NO._Fouras Calculated value: C, 63.50; H, 4.17; N, 3.89% Actual value: C, 63.28; H, 4.14; N, 3.85% Example 12 6,8-difluoro-7-(3-hydroxyph)
enyl)-1-ethyl-1,4-dihydroquino
R-4-one 3-carboxylic acid 292 mg of 6 dissolved in 50 ml of dichloromethane,
8-difluoro-7-(3-methoxyphenyl)-
1-ethyl-1,4-dihydroquinol-4-o
A solution of 3-carboxylic acid was stirred at -78°C and 8.1
ml of 1M boron tribromide-dichloromethane was added dropwise.
Ta. The reaction mixture was slowly warmed to room temperature, and 1
It was stirred overnight. Cool the mixture to 5°C and add saturated bicarbonate.
The reaction was stopped using sodium water. mixture
and extract the excess residue with hot tetrahydrofuran.
did. The organic extract was distilled off to obtain a solid residue, which was
was treated with 2M hydrochloric acid. Take the solid matter and add water
After washing and drying, the desired product is obtained as a white solid.
Ta. m.p.＞260℃ (217mg, 77% yield) NMR (DMSO−d₆, 250MHz): 9.8 (s, 1H),
9.05 (s, 1H), 8.05 (dd, 1H, J = 9Hz and 2
Hz), 7.35 (t, 1H), 6.85 (m, 2H), 4.65 (m,
2H), 3.85 (s, 3H), 1.45 (t, 3H, J=6
Hz) MS:C₁₈H₁₃F₂NO._FourAs, Calculated value: 345.0913 Actual value: 345.0856 Elemental analysis: C₁₈H₁₃F₂NO._Fouras Calculated value: C, 61.01; H, 3.95; N, 3.95% Actual value: C, 61.27; H, 3.95; N, 3.90% Example 13 A Ethyl 6,8-difluoro-7-(4-meth
xyphenyl)-1-ethyl-1,4-dihyde
quinol-4-one 3-carboxylate Following the method of Example 2, 4.67 g of 1-bromo-
4-methoxybenzene, 25ml2Mt-butyllithium
solution, 3.75 g anhydrous zinc chloride, 7.2 g ethyl 7
-Bromo-6,8-difluoro-1-ethyl-
1,4-dihydroquinol-4-one 3-carbo
xylate and 1.5 g of tetrakis (tripheni)
7.7g crude product using palladium
The product was obtained as a pale yellow solid. m.p.171−172℃ NMR (CDCl)₃, 60MHz): 8.3 (s, 1H), 8.0 (dd,
1H, J = 9Hz and 2Hz), 7.6-6.9 (m, 4H),
4.4 (2q, 4H, J=6Hz), 3.8 (s, 3H), 1.5
(t, 3H, J=6.5Hz), 1.4(t, 3H, J=6.5
Hz) MS:C_{twenty one}H₁₉F₂NO._Fouras Calculated value: 387.1279 Actual value: 387.1277 B 6,8-difluoro-7-(4-methoxyf
enyl)-1-ethyl-1,4-dihydroquino
R-4-one 3-carboxylic acid 7.7 g of crude ethyl 6,8-difluoro-7-(4
-methoxyphenyl)-1-ethyl-1,4-di
Hydroquinol-4-one 3-carboxylate
50ml of tetrahydrofuran, 100ml of 1M hydrochloric acid
The mixture was heated to reflux overnight. Cool the reaction mixture
Then, remove the formed precipitate and extract the desired product as a white solid.
(5.38 g, 75% yield). m.p.250−252℃ NMR (trifluoroacetic acid-d, 60MHz): 9.2
(s, 1H), 8.1 (dd, 1H, J=9Hz and 2Hz),
7.4 (d, 2H, J = 9Hz), 7.0 (d, 2H, J = 9
Hz), 4.8 (m, 2H), 3.9 (s, 3H), 1.6 (t,
3H, J=6.5Hz) MS:C₁₈H₁₅F₂NO._Fouras Calculated value: 359.0973, Actual value: 359.0986 Elemental analysis: C₁₈H₁₅F₂NO._Four・0.5H₂as O Calculated value: C, 61.96; H, 4.35; N, 3.80% Actual value: C, 61.78; H, 4.40; N, 3.60% Example 14 6,8-difluoro-7-(4-hydroxyph)
enyl)-1-ethyl-1,4-dihydroquino
R-4-one 3-carboxylic acid 312 mg of 6 dissolved in 40 ml of dichloromethane,
8-difluoro-7-(4-methoxyphenyl)-
1-ethyl-1,4-dihydroquinol-4-o
A solution of 3-carboxylic acid was stirred at -78°C and diluted with dichloromethane.
Drop 8.69 ml of 1M boron tribromide in lolomethane
Ta. Then slowly warm the reaction mixture to room temperature.
and stirred overnight. The reaction mixture was cooled to 5°C,
Stop the reaction by adding saturated sodium bicarbonate water.
Ta. The mixture was extracted with dichloromethane, then tet
Extracted several times with a mixture of lahydrofuran and ethyl acetate.
did. The latter extract was distilled off and the resulting solid was reduced to 1M
Stirred in hydrochloric acid for 30 minutes. Take the product and wash it with water
and dried. The desired product was obtained as a white solid.
Ta. (264 mg, 88% yield). m.p.＞270℃ NMR (DMSO−d₆, 250MHz): 9.05 (s, 1H),
8.0 (d, 1H, J = 9Hz), 7.4 (d, 2H, J = 9
Hz), 6.95 (d, 2H, J=9Hz), 4.65 (m,
2H), 1.45 (t, 3H, J=6Hz) MS:C₁₈H₁₃F₂NO._Fouras Calculated value: 345.0813, Actual value: 345.0813 Elemental analysis: C₁₈H₁₃F₂NO._Fouras Calculated value: C, 59.50; H, 4.13; N, 3.85% Actual value: C, 59.59; H, 4.07; N, 3.74% Example 15 A 4-bromobenzyldimethyl-t-butylsi
lil ether 18.7 g of 4-bromobenzyl alcohol,
Dazole (13.6g), dimethyl-t-butylsilicate
chloride (15g) and N,N-dimethylform
A solution of amide (100ml) was stirred at room temperature for 2 hours.
The reaction mixture was poured into water and extracted three times with ether.
I put it out. The combined organic extracts were washed with water and then with saline.
After cleaning, it was dried. Produced as a colorless oil after evaporation of the solvent.
I got something. This was used without further purification. NMR (CDCl)₃, 250MHz): 7.55 (d, 2H, J=9
Hz), 7.25 (d, 2H, J=9Hz), 4.7 (s, 2H),
0.9 (s, 9H), 0.0 (s, 6H) Elemental analysis: C₁₃H_{twenty one}As BrOSi Calculated value: C, 51.83; H, 6.97% Actual value: C, 51.48; H, 6.93% B Ethyl 1-ethyl-6,8-difluoro-7
-(4-t-butyldimethylsilyloxymethyl)
-phenyl)-1,4-dihydroquinol-4
-one 3-carboxylate Following the method of Example 2, 7.53 g of 4-bromobe
dimethyl-t-butylsilyl ether, 25
ml of 2M t-butyllithium solution, 3.75 g of anhydrous salt
Zinc chloride, 7.2 g ethyl 7-bromo-6,8-di
Fluoro-1-ethyl-1,4-dihydroquino
lu-4-one 3-carboxylate and 1.5 g
Tetrakis (triphenylphosphine) palladium
5.1 g (51% yield) of the title compound using a foam
Obtained as a substance. m.p.143−144℃ NMR (DMSO−d₆, 250MHz): 8.7 (s, 1H),
7.95 (dd, 1H, J = 9 and 2Hz), 7.5 (q,
4H), 4.85 (s, 2H), 4.5 (br m, 2H), 4.25
(q, 2H), 1.45 (t, 3H, J=7Hz), 1.4 (t,
3H, J=7Hz), 0.95 (s, 9H), 0.15 (s,
6H) Elemental analysis: C₂₇H₃₃F₂NO._FourAs Si Calculated value: C, 64.67; H, 6.58; N, 2.79% Actual value: C, 64.75; H, 6.72; N, 2.78% C ethyl 1-ethyl-6,8-difluoro-7
-(4-hydroxymethylphenyl)-1,4-
dihydroquinol-4-one 3-carboxylene
root 5.1g ethyl 1-ethyl-6,8-difluoro
rho-7-(4-(dimethyl-t-butyl-silyloxy)
dimethyl)-phenyl)-1,4-dihydroquino
Lu-4-one 3-carboxylate and tetra
1M tetra-n-butylammo in hydrofuran
A mixture of 10.2 ml of nium fluoride was heated at room temperature for 2 hours.
Stir for a while. Pour the reaction mixture into water and
The mixture was extracted three times with water and then once with chloroform. If
The combined extracts were dried and evaporated to produce a yellow solid product.
I got it as a thing. m.p.230-232℃ (3.8g, 96% yield
rate) NMR (DMSO−d₆, 250MHz): 8.7 (s, 1H),
7.9 (dd, 1H, J = 2Hz and 10Hz), 7.5 (s,
4H), 4.6 (d, 2H), 4.5 (m, 2H), 4.25 (q,
2H, J = 6.5Hz), 1.45 (t, 3H, J = 6.5Hz),
1.35 (t, 3H, J=6.5Hz) MS:C_{twenty one}H₁₉F₂NO._FourAs, Calculated value: 387.1279; Actual value: 387.1275 D 1-ethyl-6,8-difluoro-7-(4
-hydroxymethylphenyl)-1,4-dihy
Doroquinol-4-one 3-carboxylic acid Following the method of Example 13B, 1.5 g of ethyl 1-
Ethyl-6,8-difluoro-7-(4-hydro
(oxymethylphenyl)-1,4-dihydroquino
600 using lu-4-one 3-carboxylate
mg (43% yield) of product as a white solid.
Ta. m.p.269℃ NMR (DMSO−d₆, 250MHz): 9.05 (s, 1H),
8.05 (dd, 1H, J = 2Hz and 9Hz), 7.55 (s,
4H), 5.35 (t, 1H, J=4Hz), 4.65 (m,
2H), 4.6 (d, 2H, J=4Hz), 1.45 (t, 3H,
J=6Hz) MS:C₁₉H₁₅F₂NO._FourAs, Calculated value: 359.0965; Actual value 359.0972 Elemental analysis: C₁₉H₁₅F₂NO._Fouras Calculated value: C, 63.51; H, 4.18; N, 3.90% Actual value: C, 63.15; H, 4.21; N, 3.66% Example 16 A 3-bromobenzyldimethyl-r-butyldimethyl
lil ether 5.0 g of 3-bromobenzyl alcohol,
Dazole (3.64g), dimethyl-t-butylchloride
Rosilane (4.02g) and N,N-dimethylform
The amide (25ml) was stirred at room temperature for 2 hours. reaction mixture
The mixture was poured into water and extracted three times with ether.
The combined organic extracts were washed with water, washed with saline, and dried.
It was dry. Distillation gave the product as a colorless oil.
(6.83g, 85% yield). Use this without further purification
Ta. B Ethyl 1-ethyl-6,8-difluoro-7
-(3-dimethyl-t-butylsilyloxymethythyl
)-phenyl)-1,4-dihydroquinol-
4-one 3-carboxylate Following the method of Example 2, 6.82 g of 3-bromobe
25ml of dimethyl t-butylsilyl ether
of 2M t-butyllithium solution, 3.4g anhydrous chloride
Zinc, 5.9 g ethyl 7-bromo-6,8-diph
fluoro-1-ethyl-1,4-dihydroquinol
-4-one 3-carboxylate and 1.5 g of te
Trakis-(triphenylphosphine) palladium
7.0 g (87% yield) of product was obtained. m.
p.107−109℃ NMR (DMSO−d₆, 250MHz): 8.7 (s, 1H),
7.92 (dd, 1H, J=9 and 2Hz), 7.49 (m,
4H), 4.82 (s, 2H), 4.47 (m, 2H), 4.26 (q,
2H), 1.42 (t, 3H, J=7Hz), 1.3 (t, 3H,
J=7Hz), 0.94 (s, 9H), 0.1 (s, 6H) Elemental analysis: C₂₇H₃₃F₂NO._FourAs Si Calculated value: C, 64.67; H, 6.58; N, 2.79% Actual value: C, 64.51; H, 6.59; N, 2.75% C ethyl 1-ethyl-6,8-difluoro-7
-(3-hydroxymethylphenyl)-1,4-
dihydroquinol-4-one 3-carboxylene
root Following the method of Example 15C, 7.0 g of ethyl 1-ethyl
methyl-6,8-difluoro-7-(3-(dimethyl
-t-butylsilyloxymethyl)phenyl)-1,
4-dihydroquinol-4-one 3-carboxy
rate and 0.1M tetra in tetrahydrofuran
- using 14 ml of n-butylammonium fluoride
4.2 g (78% yield) of the product as a yellow solid.
I got it. m.p.162−166℃ NMR (DMSO−d₆, 250MHz): 8.7 (s, 1H),
7.95 (dd, 1H, J = 2Hz and 9Hz), 7.5 (m,
4H), 5.3 (t, 3H, J=6Hz), 4.6 (d, 2H,
J = 6Hz), 4.5 (m, 2H), 4.25 (q, 2H, J =
6.5Hz), 1.45 (t, 3H, J = 6.5Hz), 1.3 (t,
3H, J=6.5Hz) MS:C_{twenty one}H₁₉F₂NO._FourAs, Calculated value: 387.1279. Actual value: 387.1280 D 1-ethyl-6,8-difluoro-7-(3
-hydroxymethylphenyl)-1,4-dihy
Doroquinol-4-one 3-carboxylic acid Following the method of Example 13B, 387 mg of ethyl 1-
Ethyl-6,8-difluoro-7-(3-hydro
(oxymethylphenyl)-1,4-dihydroquino
Using lu-4-one 3-carboxylate,
330 mg (92%) of product was obtained as a white solid.
m.p.230−231℃ NMR (DMSO-d, 250MHz): 9.1 (s, 1H),
8.05 (dd, 1H, J = 9Hz and 2Hz), 7.5 (m,
4H), 4.65 (m, 2H), 4.6 (s, 2H), 1.45 (t,
3H, J=6Hz) Elemental analysis: C₁₉H₁₅F₂NO._Four・0.5H₂as O Calculated value: C, 61.95; H, 4.35; N, 3.80% Actual value: C, 61.89; H, 4.50; N, 3.48% Example 17 A Ethyl 1-ethyl-6,8-difluoro-7
-(4-azidomethylphenyl)-1,4-dihy
Droquinol-4-one 3-carboxylate 585 mg of meth dissolved in 20 ml of dichloromethane
Add a solution of sulfonyl chloride to 100 ml of dichloromethane.
15ml triethylamine dissolved in methane and
1.8g ethyl 1-ethyl-6,8-difluoro
-7-(4-hydroxymethylphenyl)-1,4
-dihydroquinol-4-one 3-carboxylene
It was added dropwise to the solution at 0°C. After dropping, the reaction mixture
The compound was extracted with 120 ml of water and the organic phase was dried.
Distillation gave mesylate product. Refine this further
Used without. Add this mesylate to 605 mg of sodium azide.
Dissolve in acetone solution and stir overnight at room temperature.
Ta. The reaction mixture was partitioned between water and dichloromethane.
The aqueous phase was extracted twice. Combined organic extract
Washed with water and saline and dried. Distilled and raw
Obtain the product and elute and purify it with a silica gel column to form a solid.
I got something. mRp.149.5−150℃ (850 mg, 44% yield
rate). NMR (DMSO−d₆, 250MHz): 8.7 (s, 1H),
7.95 (dd, 1H, J = 2Hz and 9Hz), 7.6 (ABq,
4H), 4.6 (s, 2H), 4.5 (m, 2H), 4.25 (q,
3H), J=6.5Hz), 1.45(t, 3H, J=6.5Hz),
1.35 (t, 3H, J=6.5Hz) MS:C_{twenty one}H₁₈F₂N_FourO₃as Calculated value: 412.1343, actual value: 412.1344 Elemental analysis: C_{twenty one}H₁₈F₂N_FourO₃as Calculated value: C, 61.16; H, 4.37; N, 13.59% Actual value: C, 61.65; H, 4.55; N, 13.13% B Ethyl 1-ethyl-6,8-difluoro-7
-(4-aminomethylphenyl)-1,4-dihy
Droquinol-4-one 3-carboxylate 50 ml of metal containing 1.3 g of 5% palladium on carbon.
Dissolved in a mixture of tanol and 100ml of chloroform.
2.6 g of ethyl 7-(4-azidomethylphenylene)
)-1-ethyl-6,8-difluoro-1,4
-dihydroquinol-4-one 3-carboxylene
The solution was hydrogenated for 2 hours at 12 p.s.i. anti
The reaction mixture was filtered and the liquid was evaporated. a small amount of leftovers
Grind with chloroform and dry to yield 2.2g.
The product was obtained as a solid (92%). m.p.262−263℃ NMR (DMSO−d₆, 250MHz): 8.72 (s, 1H),
8.5 (br s, 2H), 7.95 (dd, 1H, J=2 and 9
Hz), 7.65 (q, 4H), 4.49 (br m, 2H), 4.3
(q, 2H), 4.13 (s, 2H), 1.42 (t, 3H, J
= 7Hz), 1.3 (t, 3H, J = 7Hz) MS:C_{twenty one}H₂₀F₂N₂O₃as Calculated value: 386.1437 Actual value: 386.1448 C 1-ethyl-6,8-difluoro-7-(4
-aminomethylphenyl)-1,4-dihydro
Quinol-4-one 3-carboxylic hydrochloride Following the method of Example 13B, 450 mg of ethyl 7-
(4-aminomethylphenyl)-1-ethyl-6,
8-difluoro-1,4-dihydroquinol-4
-one 3-carboxylate 135mg
(79.3% yield) of product was obtained as a white solid.
m.p.＞280℃ NMR (DMSO−d₆, 250MHz): 9.1 (s, 1H),
8.1 (dd, 1H, J = 2Hz and 9Hz), 7.7 (ABqt,
4H), 4.65 (m, 2H), 4.15 (s, 2H), 1.45 (t,
3H, J=6.5Hz) MS:C₁₉H₁₆F₂N₂O₃As, Calculated value: 358.1129, Actual value: 358.1169 Elemental analysis: C₁₉H₁₆F₂N₂O₃・HCl・2H₂as O Calculated value: C, 53.02; H, 4.88; N, 6.51% Actual value: C, 53.66; H, 4.35; N, 6.60% Example 18 A Ethyl 1-ethyl-6,8-difluoro-7
-(3-azidomethylphenyl)-1,4-dihy
Droquinol-4-one 3-carboxylate Following the method of Example 17A, 25 ml of dichloromethane
1.3 g of methanesulfonyl chloride dissolved in
25 ml of the solution dissolved in 100 ml of dichloromethane
of triethylamine and 4.0 g of ethyl 1-ethyl
-6,8-difluoro-7-(3-hydroxy
methylphenyl)-1,4-dihydroquinol-
4-one in a solution of 3-carboxylate at 0 °C.
and then 5.36g of dissolved in 150ml of acetone.
Add sodium azide solution and react, 2.28
g (54% yield) of product was obtained as a solid.
m.p.119℃ NMR (DMSO−d₆, 250MHz): 8.7 (s, 1H),
7.9 (dd, 1H, J = 2Hz and 9Hz), 7.55 (m,
4H), 4.6 (s, 2H), 4.5 (m, 2H), 4.25 (q,
2H, J = 6.5Hz), 1.45 (t, 3H, J = 6.5Hz),
1.3 (t, 3H, J=6.5Hz) MS:C_{twenty one}H₁₈F₂N_FourO₃As, Calculated value: 412.1343, actual value: 412.1363 Elemental analysis: C_{twenty one}H₁₈F₂N_FourO₃as Calculated value: C, 61.16; H, 4.37; N, 13.59% Actual value: C, 61.27; H, 4.58; N, 12.77% B Ethyl 1-ethyl-6,8-difluoro-7
-(3-aminomethylphenyl)-1,4-dihy
Droquinol-4-one 3-carboxylate Following the method of Example 17B, 250 mg of ethyl 1-
Ethyl-6,8-difluoro-7-(3-didomethane)
tylphenyl)-1,4-dihydroquinol-4
-one 3-carboxylate, 200mg
(85% yield) of product was obtained as a light brown solid.
m.p.260−262℃ NMR (DMSO−d₆, 250MHz): 8.72 (s, 1H),
8.4 (brs, 2H), 7.97 (brd, 1H, J=9Hz),
7.65 (m, 4H), 4.49 (brm, 2H), 4.27 (q,
2H), 4.12 (s, 2H), 1.45 (t, 3H, J=7
Hz), 1.32 (t, 3H, J=7Hz) MS: 386 (parent ion peak), 314 (reference peak) C 1-ethyl-6,8-difluoro-7-(3
-aminomethylphenyl)-1,4-dihydro
Quinol-4-one 3-carboxylic hydrochloride Following the method of Example 13B, 450 mg of ethyl 1-
Ethyl-6,8-difluoro-7-(4-amino
Methylphenyl-1,4-dihydroquinol-4
-one 3-carboxylate 135mg
(79.3% yield) of product was obtained as a white solid.
m.p.＞280℃ NMR (DMSO−d₆, 250MHz): 9.1 (s, 1H),
8.1 (dd, 1H, J = 2Hz and 9Hz), 7.65 (m,
4H), 4.65 (m, 2H), 4.1 (s, 2H), 1.45 (t,
3H, J=6.5Hz) MS:C₁₉H₁₆F₂N₂O₃As, Calculated value: 358.1129, Actual value: 358.1172 Elemental analysis: C₁₉H₁₆F₂N₂O₃・HCl・1.5H₂O and
hand, Calculated value: C, 56.57; H, 4.46; N, 6.95% Actual value: C, 56.80; H, 4.47; N, 6.99% Example 19 3-(2-fluorophenyl)-toluene 1.46M Toluyl Magnesium Broth in Ether
Mido solution (45ml) in 70ml dry diethyl ether
10g of 2-bromofluorobenzene and 250
mg bis(diphenylphosphinoethane)-nitsu
Add to Keldichloride mixture and heat under reflux for 18 hours.
It flowed. Cool the mixture to room temperature and add 10% aqueous chloride.
Stop the reaction with ammonium water, then add 1M hydrochloric acid.
The mixture was then partitioned between ether and water. Ether the aqueous phase
The organic extracts were extracted once and the organic extracts were combined. Dry this
The crude product was obtained by drying and evaporation, and was applied to a silica gel column.
and purified by elution with hexane to produce a colorless oil.
I got something. (7.0g, 66% yield) This should be further purified.
I used it without. NMR (CDCl)₃, 60MHz): 7.4-6.9 (m, 8H), 2.4
(s, 3H). B 3-(2-fluorophenyl)-benzoic acid In 500 ml of t-butanol, 7.0 g of 3-(2-
fluorophenyl) - toluene, 29.5 g permane
A mixture of potassium ganic acid and 100 ml of water was heated at 90°C for 18
heated for an hour. Cool the reaction mixture to room temperature,
Add sufficient amount of sodium bisulfite to remove remaining
Dissolve potassium permanganate and manganese dioxide
did. The pH was adjusted to 1 with hydrochloric acid and the resulting precipitate was collected.
Dissolve this in ethyl acetate, dry and evaporate to produce
The product was obtained as a white solid. Recrystallized in hexane
After m.p. 147-148℃ (5.7g, 70% yield) NMR (DMSO−d₆, 250MHz): 8.2−7.3(m,
8H) MS:C₁₃H₉F₂₀As, Calculated value: 216.0585, Actual value: 216.0585 C 3-(2-fluoro-5-nitrophenyl)-
benzoic acid 420 mg potassium nitrate dissolved in 5 ml concentrated sulfuric acid
A solution of 1 g of 3-
(2-fluorophenyl)-benzoic acid solution at 0 °C.
The mixture was added dropwise while stirring. The mixture was stirred at 0°C for 20 minutes,
Pour into ice water. The resulting precipitate was dissolved in ethyl acetate.
The extracts were extracted and the extracts were combined. Dry this and distill it off
The product was obtained as a white solid. with ethyl acetate
m.p.272−274℃ after recrystallization NMR (DMSO−d₆, 250MHz): 8.4 (m, 2H),
8.16 (dd, 1H, J=2Hz), 8.05 (multiple
(Multiplet, 1H), 7.9 (Multiplet, 1H), 7.66
(m, 2H), 3.4 (brs, 1H) MS:C₁₃H₈NFO_FourAs, Calculated value: 261.0438, Actual value: 261.0416 Elemental analysis: C₁₃H₈NFO_Four・1/4H₂as O Calculated value: C, 58.75; H, 3.20; N-5.27% Actual value: C, 58.84; H, 3.19%N, 5.12% D 3-(2-fluoro-5-nitrophenyl)-
benzyl alcohol 1M diborane in tetrahydrofuran
Dissolve the solution (200ml) in 500ml of tetrahydrofuran.
3-(2-fluoro-5-nitrophenyl)
- Added to a solution of benzoic acid (6.6 g) under stirring.
The reaction mixture was stirred at room temperature for 12 hours and then quenched with water.
Canceled. Extract with ethyl acetate and dry the organic phase.
Removal gave a yellow solid. using a silica gel column
Purify by elution with 40% ethyl acetate/hexane.
The desired pure product was obtained as a yellow solid. (4.04g,
65% yield). m.p.113−114℃ NMR (CDCl)₃, 250MHz): 8.42 (quadruple line multi
Pret, 1H), 8.25 (octet multiplet)
g, 1H), 7.55 (m, 4H), 7.3 (quadruple line multi
Pretz, 1H), 4.8 (d, 2H, J = 4.5Hz),
0.9 (t, 1H) MS:C₁₃H_TenFNO₃As, Calculated value: 247.0645, actual value: 247,0647 Elemental analysis: C₁₃H_TenFNO₃as Calculated value: C, 63.16; H, 4.05; N, 5.67 Actual value: C, 63.42; H, 4.11; N, 5.53 E 3-(3-t-butyldimethylsilyloxime
tylphenyl)-4-fluoronitrobenzene 4.04 g of 3-(2-fluoro-5-nitrophe)
)-benzyl alcohol, 2.23 g imidazo
t-butyldimethylsilylchloride, 2.46 g
mixture of 100 ml of N,N-dimethylformamide.
The mixture was stirred at room temperature for 30 minutes. Mix the reaction mixture with water and evaporate.
and the organic phases were combined. Wash with water 3 times,
After drying and evaporation, the product was obtained as a yellow oil.
(5.9g, 99% yield). using silica gel column
Purification yielded a yellow solid. m.p.44−45℃ NMR (CDCl)₃, 250MHz): 8.4 (dd, 1H), 3.34 (8
Double line multiplet, 1H), 7.5 (m, 4H),
7.3 (m, 1H), 4.83 (s, 2H), 0.95 (s, 9H),
0.15 (s, 6H) Elemental analysis: C₁₈H_{twenty one}FNO₃As Si Calculated value: C, 63.16; H, 6.65; N, 3.88% Actual value: C, 62.99; H, 6.62; N, 3.82% F 3-(3-t-butyldimethylsilyloxime
tylphenyl)-4-fluoroaniline Dissolved in 200ml of 50% ethyl acetate/hexane
5.92g of 3-(3-tert-butyldimethylsilyloxy)
dimethylphenyl)-4-fluoronitrobenze
Using 5g of 5% palladium-carbon,
Hydrogenated for 15 minutes at 50 p.s.i. reaction mixture
The crude product was obtained by filtration and evaporation. (5.43g, 100%
yield). This was used directly without further purification. For refining
Therefore, this compound had the following data. NMR (CDCl)₃, 250MHz): 7.45 (m, 4H), 6.98
(dd, 1H), 6.75 (dd, 1H), 6.62 (octet mark
Chiplets, 1H), 4.8 (s, 2H), 3.6 (brs,
2H), 0.95 (s, 9H), 0.01 (s, 6H) MS:C₁₉H₂₉As FNOSi, Calculated value: 331.1768, Actual value: 331.1776 Elemental analysis: C₁₉H₂₉As FNOSi Calculated value: C, 68.88; H, 7.86; N, 4.23% Actual value: C, 69.15; H, 8.18; N, 4.14% G diethyl (3-(3-t-butyldimethylsilyl)
Ryloxymethylphenyl)-4-fluoronite
Roanilino) methylene malonate 5.4 g of 3-(3-t-butyldimethylsilyloxy)
dimethylphenyl)-4-fluoroaniline and
3.9ml of diethyl ethoxymethylene malonate
The mixture was heated at 150°C for 15 minutes. cool the mixture
The resulting oil was filtered with 25% vinegar using a silica gel column.
Purified by elution with ethyl acid/hexene to give a transparent light green color.
An oil was obtained. (90% yield). NMR (CDCl)₃, 250MHz): 11.1 (d, 1H, J=9
Hz), 8.5 (d, 1H, J=9Hz), 7.45 (m, 5H),
7.2 (m, 2H), 4.82 (s, 2H), 4.3 (m, 4H),
1.35 (m, 6H), 0.95 (s, 9H), 0.15 (s, 6H) MS:C₂₇H₃₆FNO_FiveAs Si, Calculated value: 501.2346, Actual value: 501.2344 Elemental analysis: C₂₇H₃₆FNO_FiveAs Si Calculated value: C, 64.67; H, 7.19; N, 2.79% Actual value: C, 64.47; H, 7.06; N, 2.97% H Ethyl 7-(3-t-butyldimethylsilyl)
(xymethylphenyl)-6-fluoro-4-hy
Droxyquinoline 3-carboxylate 18 ml of Dowtherm A, diethyl
(3-(3-t-butyldimethylsilyloxymethane)
(tylphenyl)-4-fluoronitroanilino)
A mixture of methylene malonate (2.4g) at 260℃
Heated for 2.5 hours. Cool the reaction mixture and add
The product was obtained as a white solid.
(1.13g, 52% yield). m.p.310−312℃ (decomposition) NMR (1% DMSO-d₆/TFA-d, 250M
Hz): 9.4 (a, 1H), 8.38 (m, 2H), 7.83 (m,
2H), 7.65 (m, 2H), 5.55 (s, 2H), 5.0 (s,
1H), 4.68 (q, 2H), 1.55 (t, 3H), 1.01 (s,
9H), 0.4(s, 6H) I Ethyl 7-(3-t-butyldimethylsilyl)
(oxymethylphenyl)-1-ethyl-6-fur
Oro-1,4-dihydroquinol-4-one 3
-carboxylate 1.13 in 50 ml of N,N-dimethylformamide
g of ethyl 7-(3-t-butyldimethylsilyl)
(oxymethylphenyl)-6-fluoro-4-hydro
Roxyquinoline 3-carboxylate, 3ml
Add a mixture of udoethane and 1.5 g potassium carbonate to the chamber.
Stir at room temperature for 24 hours. The reaction mixture was mixed with water and ethyl acetate.
The ethyl acetate phase was washed with water four times. drying
and evaporated to obtain a crude product, which was purified by silica gel.
Purify the column by eluating with ethyl acetate/hexane.
The pure product was obtained as a pale yellow oil.
(1.02g, 85% yield) NMR (CDCl)₃, 250MHz): 8.55 (s, 1H), 8.3
(d, 1H, J=11Hz), 7.5 (m, 5H), 4.85 (s,
2H), 4.45 (q, 2H, J = 6.5Hz), 4.3 (q, 3H,
J = 6.5Hz), 1.6 (t, 3H, J = 6.5Hz), 1.45
(t, 3H, J=6.5Hz), 1.0 (s, 9H), 0.0 (s,
6H) J Ethyl 1-ethyl-6-fluoro-7-(3
-hydroxymethylphenyl)-1,4-dihy
Droquinol-4-one 3-carboxylate 1M tetra-n-buty in tetrahydrofuran
ammonium fluoride solution (2.11 ml), 20
1.02 g of ethyl alcohol dissolved in ml of tetrahydrofuran
7-(3-t-butyldimethylsilyloxymethythyl)
(ruphenyl)-1-ethyl-6-fluoro-1,
4-dihydroquinol-4-one 3-carboxy
Added to the solution of rate. After 15 minutes, dissolve the solution in ethyl acetate.
and water, and the organic extract was dried. leave
The product was obtained as a white solid (755 mg, 97%
yield). K 1-ethyl-6-fluoro-7-(3-hydro
(roxymethylphenyl)-1,4-dihydroxy
Nol-4-one 3-carboxylic acid 755 mg ethyl 1-ethyl-6-fluoro-7
-(3-hydroxymethylphenyl)-1,4-di
Hydroquinol-4-one 3-carboxylate
50 ml of 1M sodium hydroxide solution, 5 ml of Tet
The mixture of lahydrofuran was heated at 90°C for 30 minutes.
The solution was cooled and brought to PH1 with 6M hydrochloric acid. The resulting sink
The lees were removed, washed with water, and then dried. The product is a white solid
I got it as a thing. m.p.203−204℃ (587mg, 84% yield)
rate). NMR (DMSO−d₆, 250MHz): 9.1 (s, 1H),
8.1 (m, 2H), 7.5 (m, 4H), 4.7 (q, 2H),
4.6 (d, 2H, J = 7Hz), 1.45 (t, 3H, J =
6.5Hz) MS:C₁₉H₁₆FNO_FourAs, Calculated value: 341.1064, Actual value: 341.1060 Elemental analysis: C₁₉H₁₆FNO_Four・0.25H₂as O Calculated value: C, 65.99; H, 4.78; N, 4.05% Actual value: C, 66.09; H, 5.16; N, 3.91% Example 20 A 4-(2-fluorophenyl)-toluene Following the method of Example 19A, 10 g of 2-bromof
fluorobenzene, 250 mg bis(diphenylphos)
finylethane) nickel dichloride and 89ml
Using 0.73M4-toluylmagnesium bromide
6.0 g (57% yield) of product was obtained. This product has been updated
It was used without further purification. NMR (CDCl)₃, 60MHz): 7.5-6.9 (m, 8H), 2.3
(s, 3H) B 4-(2-fluorophenyl)-benzoic acid Following the method of Example 19B, 1.0 g of 4-(2-
(fluorophenyl) - using toluene, 1.17g
(100% yield) of product was obtained as a white solid.
m.p.226−227℃ NMR (DMSO−d₆, NHz): 8.1 (d, 2H), 7.8
−7.3 (m, 6H) C4-(2-fluoro-5-nitrophenyl)
benzoic acid 1.0 g of 4-(2-fur) according to the method of Example 19C.
1.2g (100%) using benzoic acid
Yield) of the product was obtained as a white solid. m.p.＞
280℃ NMR (DMSO−d₆, 250MHz): 8.5−7.6(m,
7H) MS:C₁₃H₈NFO_FourAs, Calculated value: 261.0438, Actual value: 261.0457 D 4-(2-fluoro-5-nitrophenyl)-
benzyl alcohol Following the method of Example 19D, 1.2 g of 4-(2-
using fluoro-5-nitrophenyl)benzoic acid
700 mg (61% yield) of the product as a pale yellow solid.
obtained as. m.p.106−108.5℃ NMR (CDCl)₃, 250MHz): 8.4 (m, 1H), 8.2 (m,
1H), 7.55 (ABq, 4H), 7.3 (m, 1H), 4.8
(d, 2H, J=6Hz) E 3-(4-t-butyldimethylsilyloxy
methylphenyl)-4-fluoronitrobenze
hmm Following the method of Example 19E, 4.2 g of 4-(2-
fluoro-5-nitrophenyl)-benzylalco
2.5 g imidazole and 3.5 g t-butyl
6.0g (98% yield) from tildimethylsilyl chloride
%) product was obtained. This oil is not further refined.
It was used for. F 3-(4-t-butyldimethylsilyloxy
methylphenyl)-4-fluoroaniline Following the method of Example 19F, 6.0 g of 3-(4-t
-butyldimethylsilyloxymethylphenyl)
-Production of 5.5g from 4-fluoronitrobenzene
I got something. The resulting oil can be used without further purification.
Ta. G diethyl (3-(4-t-butyldimethylsilyl)
(lyloxymethylphenyl)-4-fluoroni
troanilino) methylene malonate Following the method of Example 19G, 5.5 g of 3-(4-t
-butyldimethylsilyloxymethylphenyl)
-4-fluoroaniline and 3.5 ml diethyl
5.12g (60% yield) from ethoxymethylene malonate
%) product was obtained. A pale yellow-green oil was obtained. NMR (CDCl)₃, 250MHz): 8.5 (d, 1H, J=12
Hz), 7.5 (ABq, 4H), 7.2 (m, 3H), 4.8 (s,
2H), 4.25 (m, 4H), 1.35 (m, 6H), 1.0 (s,
9H), 0.1(s, 6H) H Ethyl 7-(4-t-butyldimethylsilyl
(oxymethylphenyl)-6-fluoro-4-
Hydroxyquinoline 3-carboxylate Following the method of Example 19H, 1.0 g of diethyl
(3-(4-t-butyldimethylsilyloxymethylene)
(ruphenyl)-4-fluoroanilino)methylene
379 mg (42% yield) of product was obtained from malonate.
Ta. A white solid with a melting point of 280°C or higher was obtained. I Ethyl 7-(4-t-butyldimethylsilyl
(oxymethylphenyl)-1-ethyl-6-phenyl
fluoro-1,4-dihydroquinol-4-one
3-carboxylate 379 mg of ethyl 7-(4
-t-butyldimethylsilyloxyphenyl)-
6-Fluoro-4-hydroxyquinoline 3-cal
233 mg (58% yield) of product from boxylate
Obtained as a solid with a melting point of 158-160°C. NMR (CDCl)₃, 250MHz): 8.5 (s, 1H), 8.2 (d,
1H, J=11Hz), 7.5 (ABq, 4H), 7.45 (d,
1H), 4.8 (s, 2H), 4.4 (q, 2H, J=6.5Hz),
4.3 (q, 2H, J = 6.5Hz), 1.55 (t, 3H, J =
6.5Hz), 1.4 (t, 3H, J = 6.5Hz), 1.0 (s,
9H), 0.1(s, 6H) J Ethyl 1-ethyl-6-fluoro-7-(4
-hydroxymethylphenyl)-1,4-dihy
Droquinol-4-one 3-carboxylate Following the method of Example 19J, 230 mg of ethyl 7-
(4-t-butyldimethylsilyloxymethyl phthalate)
enyl)-1-ethyl-6-fluoro-1,4-
Dihydroquinol-4-one 3-carboxylate
170 mg (97% yield) of the product was obtained as a white solid.
This product was used without further purification. K 1-ethyl-6-fluoro-7-(4-hydro
(roxymethylphenyl)-1,4-dihydroxy
Nol-4-one 3-carboxylic acid Following the method of Example 19K, 170 mg of ethyl 1-
Ethyl-6-fluoro-7-(4-hydroxymeth)
tylphenyl)-1,4-dihydroquinol-4
155 mg (95% yield) from -one 3-carboxylate
%) product was obtained. from dimethylformamide
Recrystallization gave a white solid with a melting point of 220-221°C. NMR (DMSO−d₆, 250MHz): 9.1 (s, 1H),
8.1 (dd, 2H), 8.6 (ABq, 4H), 4.7 (q, 2H),
4.6 (s, 2H), 1.45 (t, 3H, J = 6.5Hz). Example 21 A Ethyl 1-ethyl-6-fluoro-7-(4
-formylphenyl)-1,4-dihydroquino
R-4-one 3-carboxylate Ethyl 1-ethyl-6-fluoro-7-(4-
Hydroxymethylphenyl)-1,4-dihydro
Quinol-4-one 3-carboxylate (450
mg) of dichloromethane (8 ml) and dimethyls
Oxalyl in sulfoxide (2 ml) solution at -78°C.
Chloride (171 mg) was added dropwise. After 25 minutes, 0.9ml
Add triethylamine and heat the mixture to room temperature.
Warm and partition between water and ethyl acetate. organic layer
Dry and concentrate to a small volume. With diethyl ether
The product becomes a white solid with a melting point of 165-170℃.
(360 mg, 80% yield). NMR (CDCl)₃, 250MHz): 1.01 (s, 1H), 8.55
(s, 1H), 8.3 (d, 1H), J=11Hz), 8.0 (d,
2H, J=9Hz), 7.75 (d, 2H, J=9Hz),
7.5 (d, 1H, J=6Hz), 4.4 (2q, 4H), 1.6
(t, 3H, J=6.5Hz), 1.45 (t, 3H, J=6.5
Hz). MS:C_{twenty one}H₁₈NO._Fouras F Calculated value: 367.1220, Actual value: 367.1230 B Ethyl 1-ethyl-6-fluoro-7-(4
-formylphenyl)-1,4-dihydroquino
R-4-one 3-carboxylic acid Following the method of Example 19K, 110 mg of ethyl 1-
Ethyl-6-fluoro-7-(4-formylphene)
Nyl)-1,4-dihydroquinol-4-one 3
-Production of 63 mg (62% yield) from carboxylate
The product was obtained as a white solid with a melting point >270°C. NMR (DMSO−d₆/trifluoroacetic acid-d,
250MHz): 9.45 (s, 1H), 8.5 (d, 1H, J=
11Hz), 8.4 (d, 1H, J = 6Hz), 8.2 (d, 2H,
J = 9Hz), 8.0 (d, 2H, J = 9Hz), 5.0 (m,
2H), 1.8 (t, 3H, J = 6.5Hz). MS:C₁₉H₁₄R.N.O._Fouras Calculated value: 339.0908, Actual value: 339.0872 Elemental analysis: C₁₉H₁₄FNO_Fouras Calculated value: C, 67.26; H, 4.13; N, 4.13% Actual value: C, 67.08; H, 4.45; N, 4.04% Example 22 A 4-bromo-2-chloroanisole 4-Bromo-2-chlorophenol (5.18g)
A solution of sodium hydride in tetrahydrofuran (20 ml)
Tetrahydrofuran with Limeium (0.72g)
(50 ml) into the stirred mixture. Iodine after 30 minutes
Add methane (4.26g) and let the mixture stand overnight at room temperature.
Stirred. Add another 7.1g of iodomethane,
The mixture was heated to reflux overnight. Then the reaction mixture is
Partitioned between water and chloroform. combined organic
The extract was dried, evaporated and washed with hexane.
The product was obtained as a white solid with m.p. 63 °C (5.4
g, 98% yield). Elemental analysis: C₇H₆As BrClO Calculated value: C, 38.00; H, 2.71% Actual value: C, 38.07; H, 2.80% B Ethyl 1-ethyl-7-(3-chloro-4-
methoxyphenyl)-6,8-difluoro-1,
4-dihydroquinol-4-one 3-carboxy
Sylate Following the method of Example 2, 1.11 g of 4-bromo-
2-chloroanisole, 5 ml 2Mt-butyl lithium
solution, 750 mg zinc chloride and 720 mg ethyl
7-bromo-6,8-difluoro-1-ethyl-
1,4-dihydroquinol-4-one 3-carbo
Xylate and 100mg Tetrakis (Trifue
Nilphosphine) 300mg with palladium
(35.5% yield) of product was obtained. Yellow with melting point 280℃
A solid was obtained. NMR (CDCl)₃, 250MHz): 8.45 (s, 1H), 8.15
(dd, 1H, J=2Hz and 9Hz), 7.55(s,
1H), 7.4 (m, 1H), 7.1 (d, 1H, J=9Hz),
4.4 (2q, 4H), 4.0 (s, 3H), 1.55 (t, 3H, J
= 6.5Hz), 1.45 (t, 3H, J = 6.5Hz). Elemental analysis: C_{twenty one}H₁₈ClF₂NO._Four・0.5H₂as O Calculated value: C, 58.00; H, 4.41; N, 3.25% Actual value: C, 59.06; H, 4.52; N, 3.17% C7-(3-chloro-4-methoxyphenyl)-
6,8-difluoro-1-ethyl-1,4-di
Hydroquinol-4-one 3-carboxylic acid Following the method of Example 13B, 300 mg of ethyl 1-
Ethyl-7-(3-chloro-4-methoxyphenylene)
)-6,8-difluoro-1,4-dihydroxy
250 from nor-4-one 3-carboxylate
mg (90% yield) of product was obtained. Melting point>280℃
A white solid was obtained. Elemental analysis: C₁₉H₁₄ClF₂NO._Four・1/3H₂as O Calculated value: C, 57.14; H, 3.67; N, 3.50% Actual value: C, 57.16; H, 3.69; N, 3.22% NMR (DMSO−d₆, 250MHz): 9.05 (s, 1H),
8.05 (dd, 1H, 9Hz and 2Hz), 7.7 (s,
1H), 7.55 (m, 1H), 7.35 (d, 1H, J=9
Hz), 4.65 (m, 2H), 3.95 (s, 3H), 1.45 (t,
3H, J = 6.5Hz). Example 23 7-(3-chloro-4-hydroxyphenyl)-
6,8-difluoro-1-ethyl-1,4-di
Hydroquinol-4-one 3-carboxylic acid Following the method of Example 14, 200 mg of 7-(3-chloro)
lo-4-methoxyphenyl)-6,8-difluoro
rho-1-ethyl-1,4-dihydroquinol-4
-one 40 mg (21% yield) of 3-carboxylic acid
A product was obtained. Yellow solid, melting point 235-238°C. NMR (DMSO−d₆, 250MHz): 9.05 (s, 1H),
8.05 (dd, 1H, J=2Hz and 9Hz), 7.65
(s, 1H), 7.4 (d, 1H, J=9Hz), 7.15 (d,
1H, J=9Hz), 4.65 (m, 2H), 1.45 (t,
3H, J = 6.5Hz). MS:C₁₈H₁₂ClF₂NO._Fouras Calculated value: 379.0423, Actual value: 379.0423 Example 24 A Ethyl 6,8-difluoro-1-ethyl-7
-(2-methoxyphenyl)-1,4-dihydro
Quinol-4-one 3-carboxylate Following the method of Example 2, 935 mg of 2-bromore
Nisole, 5 2Mt-butyllithium, 818mg
Anhydrous zinc chloride, 720 mg ethyl 7-bromo-6,
8-difluoro-1,4-dihydroquinol-4
-one 3-carboxylate and 248 mg tet
Rakis (triphenylphosphine) palladium
504 mg (65% yield) of product was obtained. NMR (CDCl)₃, 250MHz): 8.4 (s, 1H), 8.0 (dd,
1H, J=2Hz and 9Hz), 7.2 (m, 4H), 4.4
(2q, 4H), 3.8 (s, 3H), 1.5 (t, 3H, J=
6Hz), 1.4 (t, 3H, J = 6Hz). MS:C_{twenty one}H₁₉F₂NO._Fouras Calculated value: 387.1285, actual value: 387.1306 B 6,8-difluoro-1-ethyl-7-(2
-methoxyphenyl)-1,4-dihydroquino
R-4-one 3-carboxylic acid Following the method of Example 1F, 500 mg of ethyl 6,8
-difluoro-1-ethyl-7-(2-methoxy
phenyl)-1,4-dihydroquinol-4-o
343 mg (74% yield) from carbon 3-carboxylate
The product was obtained as a white solid with a melting point >260°C. Elemental analysis: C₁₉H₁₅F₂NO._Four・1H₂as O Calculated value: C, 60.47; H, 4.50; N, 3.71% Actual value: C, 60.73; H, 4.17; N, 3.82% NMR (DMSO−d₆, 250MHz): 9.05 (s, 1H),
8.05 (dd, 1H, J=2Hz and 9Hz), 7.55
(m, 1H), 7.45 (d, 1H, J=9Hz), 7.25
(d, 1H, J=9Hz), 7.15 (m, 1H), 4.65
(m, 2H), 3.8 (s, 3H, 1.45 (t, 3H, J=
6.5Hz). MS:C₁₉H₁₅F₂NO._Fouras Calculated value: 359.0969, Actual value: 359.0963 Example 25 6,8-difluoro-1-ethyl-7-(2-
Hydroxyphenyl)-1,4-dihydroquino
R-4-one 3-carboxylic acid Following the method of Example 12, 310 mg of 6,8-diph
fluoro-1-ethyl-7-(2-methoxyphenylene)
)-1,4-dihydroquinol-4-one 3-
135 mg (45% yield) of product was obtained from the carboxylic acid.
A cream solid with a melting point >260°C was obtained. Elemental analysis: C₁₈H₁₃F₂NO._Four・1/4H₂as O Calculated value: C, 61.80; H, 3.71; N, 4.00% Actual value: C, 61.54; H, 3.98; N, 3.91% NMR (DMSO−d₆, 250MHz): 10(br s,
1H), 9.1 (s, 1H), 8.05 (dd, 1H, J=2Hz
and 9Hz), 7.35 (m, 2H), 7.0 (m, 2H),
4.65 (m, 2H), 1.45 (t, 3H, J = 6Hz). MS:C₁₈H₁₃F₂NO._Fouras Calculated value: 345.0911, Actual value: 345.0911 Example 26 A 3-bromo-4-fluoroaniline Following the method of Example 1B, 13 g of 3-bromo-
10.68g (95%) from 4-fluoronitrobenzene
yield) of the product was obtained. The product is an oil and
It was used without further purification. NMR (CDCl)₃, 250MHz): 6.9 (m, 2H), 6.6 (m,
1H). B Ethyl 7-bromo-6-fluoro-4-hydro
Roxyquinoline 3-carboxylate Following the method of Example 1C, 10 g of 3-bromo-
4-fluoroaniline and 11.36 g diethyl
Production of 8.8g (55% yield) from ethoxymethylene
I got something. A white solid was obtained with a melting point >280°C. NMR (DMSO−d₆/trifluoroacetic acid-d,
250MHz): 9.35 (s, 1H), 8.6 (d, 1H, J=
6Hz), 8.3 (d, 1H, J=11Hz), 4.65 (q,
2H, J = 6.5Hz), 1.5 (t, 3H, J = 6.5Hz). MS:C₁₂H₉FBrNO₃as Calculated value: 312.9759, Actual value: 312.9766 C ethyl 7-bromo-1-ethyl-6-fluoro
rho-1,4-dihydroquinol-4-one 3-
carboxylate Following the method of Example 1D, 8.6 g of ethyl 7-butyl
lomo-6-fluoro-4-hydroxyquinoline 3
- 5.2 g (55% yield) of raw material from carboxylate
A product was obtained. White solid, melting point 149-150°C. NMR (CDCl)₃, 250MHz): 8.45 (s, 1H), 8.15
(d, 1H, J=11Hz), 7.7(d, 1H, J=6
Hz), 4.4 (q, 2H, J=6.5Hz), 4.2 (q, 2H,
J = 6.5Hz), 1.55 (t, 3H, J = 6.5Hz), 1.4
(t, 3H, J = 6.5Hz). MS:C₁₄H₁₃BrFNO₃as Calculated value: 341.0062, Actual value: 341.0023 D Ethyl 1-ethyl-6-fluoro-7-(4
-methoxyphenyl)-1,4-dihydroquino
R-4-one 3-carboxylate Following the method of Example 13A, 500 mg of 4-bromo
Anisole, 2.67ml 2Mt-butyllithium,
500mg anhydrous zinc chloride, 608mg ethyl 7-bromo
-1-ethyl-6-fluoro-1,4-dihydro
Quinol-4-one 3-carboxylate and
300mg Tetrakis (Triphenylphosphine)
422 mg (64% yield) of product was obtained from palladium.
Ta. Yellow solid m.p. 215-218°C. NMR (CDCl)₃, 250MHz): 8.45 (s, 1H), 8.2
(d, 1H, J=11Hz), 7.55 (dd, 2H, J=9
Hz and 2Hz), 7.45 (d, 1H, J = 6Hz), 7.0
(d, 2H, J = 9Hz), 4.4 (q, 2H, J = 6.5
Hz), 4.3 (q, 2H, J=6.5Hz), 3.9 (s, 3H),
1.6 (t, 3H, J = 6.5Hz), 1.45 (t, 3H, J =
6.5Hz). E 1-ethyl-6-fluoro-7-(4-meth
xyphenyl)-1,4-dihydroquinol-
4-one 3-carboxylic acid (R₁=R₂=H; Y=ethyl; R₃=4-Methoki
(Sifenil) Following the method of Example 13B, 400 mg of ethyl 1-
Ethyl-6-fluoro-7-(4-methoxyphene)
Nyl)-1,4-dihydroquinol-4-one 3
- 355 mg (96% yield) of raw material from carboxylate
A product was obtained. White solid, m.p. 279-282°C. NMR (DMSO−d₆/trifluoroacetic acid-d,
250MHz): 9.4 (s, 1H), 8.4 (d, 1H, J=11
Hz), 8.3 (d, 1H, J=6Hz), 7.75 (d, 2H,
J = 9Hz), 7.2 (d, 2H, J = 9Hz), 5.0 (m,
2H), 4.0 (s, 3H), 1.8 (t, 3H, J = 6.5Hz). MS:C₁₉H₁₆FNO_Fouras Calculated value: 341.1064, Actual value: 341.1057 Elemental analysis: C₁₉H₁₆FNO_Fouras Calculated value: C, 65.14; H, 4.86; N, 4.00% Actual value: C, 65.19; H, 4.74; N, 3.91% Example 27 1-ethyl-6-fluoro-7-(4-hydro
xyphenyl)-1,4-dihydroquinol-
4-one 3-carboxylic acid Following the method of Example 14, 300 mg of 1-ethyl-
6-Fluoro-7-(4-methoxyphenyl)-
1,4-dihydroquinol-4-one 3-carbo
276 mg (96% yield) of product was obtained from phosphoric acid. m.
p.>280℃ yellow solid. NMR (DMSO−d₆/trifluoroacetic acid-d,
250MHz): 9.0 (, 1H), 8.0 (d, 1H, J = 11
Hz), 7.85 (d, 1H, J=6Hz), 7.3 (d, 2H,
J=9Hz), 6.75 (d, 2H, J=9Hz), 4.55
(m, 2H), 1.4 (t, 3H, J = 6Hz). MS:C₁₈H₁₄FNO_Fouras Calculated value: 327.0907, Actual value: 327.0930 Elemental analysis: C₁₈H₁₄FNO_Four・1/8H₂as O Calculated value: C, 65.60; H, 4.32; N, 4.25% Actual value: C, 65.65; H, 4.43; N, 4.10% Example 28 Ethyl 1-ethyl-6-fluoro-7-phenylene
Ru-1,4-dihydroquinol-4-one 3-
carboxylate Following the method of Example 1E, 0.72 ml of 1.83M
rulithium, 300 mg ethyl 7-bromo-6-ph
fluoro-1,4-dihydroquinol-4-one 3
- Carboxylate, 192 mg zinc chloride and 104
mg tetrakis (triphenylphosphine) para
173 mg (51% yield) of product was obtained using
Ta. This sample was synthesized in all respects as in Example 4E.
It was the same as the sample. MS:C₂₀H₁₈FNO₃as Calculated value: 339.1271, Actual value: 339.1257 Example 29 Ethyl 7-(4-t-butyldimethylsilyl)
(oxymethylphenyl)-1-ethyl-6-fur
Oro-1,4-dihydroquinol-4-one 3
-carboxylate Following the method of Example 2, 1.51 g of 4-bromobe
silyldimethyl-t-butylsilyl ether,
6.72ml (2M) t-butyllithium, 818mg salt
Zinc chloride, 684 mg ethyl 7-bromo-1-ethyl
-6-fluoro-1,4-dihydroquinol-4
-one 3-carboxylate and 231 mg tet
Rakis (triphenylphosphine) palladium?
301 mg (31% yield) of product was obtained. sample lotus
Compared to the sample synthesized in Example 15B in all respects.
They were the same. NMR (CDCl)₃, 250MHz): 8.5 (s, 1H), 8.25
(d, 1H), 7.5 (q, 4H), 6.9 (d, 1H), 4.8
(s, 2H), 4.4 (q, 2H), 4.3 (q, 2H), 1.58
(t, 3H, J = 7Hz), 1.42 (t, 3H, J = 7
Hz), 0.95 (s, 9H), 0.1 (s, 6H). MS:C_{twenty two}H₃₄FNO_FourAs Si Calculated value: 483.2241, Actual value: 483.2241 Example 30 Ethyl 7-(3-t-butyl-dimethylsilyl)
(oxymethylphenyl)-1-ethyl-6-phenyl
fluoro-1,4-dihydroquinol-4-one
3-carboxylate Following the method of Example 2, 602 mg of 3-bromobe
silyldimethyl-t-butylsilyl ether,
1.64ml (1.28M) t-butyllithium, 341mg
of zinc chloride, 342 mg of ethyl 7-bromo-1-ethyl
Chil-6-fluoro-1,4-dihydroquinol
-4-one 3-carboxylate and 115 mg of
Tetrakis (triphenylphosphine) palladium
280 mg (58% yield) of product was obtained from the sample. Main exam
The material was synthesized in all respects in Example 16B.
It is the same as the thing. NMR (CDCl)₃, 90MHz): 8.6 (s, 1H), 8.3 (d,
1H), 7.5 (m, 5H), 4.9 (s, 2H), 4.45 (q,
4H), 1.5 (quintet m, 6H), 0.95 (s, 9H),
0.1 (s, 6H). MS:C₂₇H₃₄FNO_FourAs Si Calculated value: 483.2241, Actual value: 483.2195 Example 31 A Ethyl 7-bromo-6,8-difluoro-1
-(2-fluoroethyl)-1,4-dihydroxy
Nol-4-one 3-carboxylate Following the method of Example 1D, ethyl 7-bromo-
6,8-difluoro-4-hydroxyquinoline-
3-carboxylate (5.0 g, 15 mmol), none
Potassium hydrcarbonate (4.2 g, 30 mmol), 1-Flu
oro-2-bromo-ethane (25g, 15ml, 200mg
limol) in dimethylformamide solution.
Then, recrystallize from 2-propanol to obtain a white solid.
(3.3 g, 58% yield) m.p. 185-187°C; IR (CHCl₃, cm-1): 1732 (s), 1695 (s),
1461(s); NMR (CDCl)₃, 250MHz): 8.39 (s, 1H), 8.14
(dd, 1H, J=10, 4Hz), 4.95−4.85(m,
2H), 4.78−4.55 (m, 2H), 4.40 (q, 2H, J
= 7Hz), 1.40 (t, 3H, J = 7Hz). Elemental analysis: C₁₄H₁₁BrF₃NO.₃as Calculated value: C, 44.49; H, 2.93; N, 3.71; Br,
21.14; F, 15.08% Actual value: C, 44.35; H, 2.98; N, 3.64; Br,
21.50; F, 14.65% B Ethyl 6,8-difluoro-7(4-methoxy)
Cyphenyl)-1-(2-fluoroethyl)-1,
4-dihydroquinol-4-one 3-carboxy
Sylate Following the method of Example 2, ethyl 7-bromo-
6,8-difluoro-1-(2-fluoroethyl)
-1,4-dihydroquinol-4-one 3-cal
Boxylate (1.0 g, 2.7 mmol), 1-bro
Mo-4-methoxybenzene (1.24g, 0.83ml, 6.6
mmol), t-butyllithium n-pentane
Solution (1.8M, 7.4ml, 13.3mmol) anhydrous sodium chloride
Lead (1.1 g, 8.0 mmol) and tetrakis
rifenylphosphine) palladium (306mg)
The crude product was obtained as a yellow solid. S
Chromatograph on lica gel with ethyl acetate as eluent
A solid was obtained by roughy. (507 mg, 47% yield
rate) m.p.193−195℃; IR (KBr, cm-1): 1726 (s), 1612 (s), 1575
(m), 1541 ((m), 1518 (m); NMR (CDCl)₃, 250MHz): 8.42 (s, 1H), 8.16
(dd, 1H, J = 10, 4Hz), 7.43 (d, 2H, J
= 9Hz), 7.05 (d, 2H, J = 9Hz), 4.95-
4.65 (m, 4H), 4.42 (q, 2H, J=7Hz),
3.91 (s, 3H), 1.42 (t, 3H, J=7Hz). Elemental analysis: C_{twenty one}H₁₈F₃NO._Four・H₂as O Calculated value: C, 59.57; H, 4.76; N, 3.31% Actual value: C, 59.83; H, 4.33; N, 3.28% C 6,8-dihydro-7-(4-methoxyphene
Nyl)-1-(2-fluoroethyl)-1,4-
Dihydroquinol-4-one 3-carboxylic acid Following the method of Example 13B, ethyl 6,8-diphthyl
fluoro-7-(4-methoxyphenyl)-1-(2
-fluoroethyl)-1,4-dihydroquinol
-4-one 3-carboxylate (275 mg, 0.7 mi)
(191
mg, 75% yield); m.p.>270℃; IR (KBr, cm-1): 1720 (s), 1621 (s), 1612
(s); NMR (1% DMSO-d₆/CF₃C.O.₂D，250M
Hz): 8.90 (s, 1H), 7.90 (d, 1H, J=9
Hz), 7.22 (d, 2H, J=10Hz), 6.80 (d, 2H,
J=10Hz), 4.95 (br.d, 2H, J=24Hz), 4.65
(d, 2H, J=45Hz), 3.57 (s, 3H). Elemental analysis: C₁₉H₁₄F₃NO._Four・0.75H₂as O Calculated value: C, 58.39; H, 3.99; N, 3.58% Actual value: C, 58.12; H, 3.75; N, 3.38% Example 32 6,8-difluoro-7-(4-hydroxyph)
enyl)-1-(2-fluoroethyl)-1,4
-dihydroquinol-4-one 3-carboxylic acid Following the method of Example 14, 6,8-difluoro-
7-(4-methoxyphenyl)-1-(2-fluoro
loethyl)-1,4-dihydroquinol-4-o
3-carboxylic acid (200 mg, 0.53 mmol) and
and boron tribromide in methylene chloride solution (1M,
5.3 ml, 5.3 mmol) was reacted, and the crude product was
Obtained as a yellow solid. White when ground in boiling water
A solid was obtained (131 mg, 66% yield); m.p.>280
℃; IR (KBr, cm^-1): 1724(s), 1610(s), 1589
(s), 1567 (m); NMR (1% DMSO-d₆/CF₃C.O.₂D，250M
Hz): 9.35 (s, 2H), 8.34 (d, 1H, J=10
Hz), 5.38 (d, 2H, J=24Hz), 5.00 (d, 2H,
J=45Hz); MS:C₁₈H₁₂F₃NO._Fouras Calculated value: 363.0719, Actual value: 363.0709 Elemental analysis: C₁₈H₁₂F₃NO._Four・H₂as O Calculated value: C, 56.70; H, 3.70; N, 3.67% Actual value: C, 56.99; H, 3.45; N, 3.67% Example 33 A Ethyl 7-bromo-6,8-difluoro-1
-Methyl-1,4-dihydroquinol-4-o
3-carboxylate Following the method of Example 1D, ethyl 7-bromo-
6,8-difluoro-4-hydroquinoline-3-
Carboxylate (5.0 g, 15 mmol), anhydrous charcoal
Potassium acid (4.16g, 30mmol) and iodine
Methane (6.4 g, 2.8 ml, 45 mmol) in dimethyl
Reacted in formamide (50 ml) and 2-propyl
Recrystallization from alcohol gave a white solid (3.4 g,
66% yield); m.p. 174−175℃; IR (CHCl₃,cm^-1); 1732 (s), 1963 (s), 1642
(s), 1611(s); NMR (CDCl)₃, 250MHz): 8.40 (s, 1H), 8.00
(dd, 1H, J=10.4Hz), 4.35(q, 2H, J=7
Hz), 4.08 (d, 3H, J=8Hz), 1.58 (t, 3H,
J=7Hz). Elemental analysis: C₁₃H_TenBrF₂NO.₃as Calculated value: C, 45.13; H, 2.92; N, 4.05; Br,
23.10; F, 10.98% Actual value: C, 45.05; H, 2.70; N, 4.01; Br,
22.83; F, 10.52% B Ethyl 6,8-difluoro-7-(4-meth
xyphenyl)-1-methyl-1,4-dihyde
quinol-4-one 3-carboxylate Following the method of Example 2, ethyl 7-bromo-
6,8-difluoro-1-methyl-1,4-dihydrogen
Droquinol-4-one 3-carboxylate
(1.0 g, 2.9 mmol), 1-bromo-4-methoxy
Sibenzene (1.35g, 0.91ml, 7.3mmol), t
-Butyllithium in pentane solution (1.8M, 8.1
ml, 14.6 mmol) and anhydrous zinc chloride (1.31
g, 9.6 mmol) and tetrakis (trihue
Nylphosphine) palladium (306 mg) was reacted with
The crude product was obtained as a yellow solid. silica
Column chromatography with ethyl acetate on gel
A solid was obtained (624 mg, 57% yield); m.
p.176−178℃; IR (KBr, cm^-1): 1733 (m), 1684 (s), 1639
(s), 1617 (s), 1540 (m); NMR (CDCl)₃, 250MHz): 8.38 (s, 1H), 8.08
(dd, 1H, J = 10, 4Hz), 7.42 (d, 2H, J
= 8Hz), 7.05 (d, 2H, J = 8Hz), 4.41 (q,
2H, J = 7Hz), 4.12 (d, 3H, J = 8Hz),
3.90 (s, 3H), 1.42 (t, 3H, J=7Hz); MS (m/e), 373 (parent ion peak), 201 (standard
peak) Elemental analysis: C₂₀H₁₃F₂NO._Four・0.4H₂as O Calculated value: C, 62.83; H, 4.74; N, 3.66% Actual value: C, 63.22; H, 4.77; N, 3.42% C 6,8-difluoro-7-(4-methoxyf
enyl)-1-methyl-1,4-dihydroquino
R-4-one 3-carboxylic acid Following the method of Example 13B, ethyl 6,8-diphthyl
fluoro-7-(4-methoxyphenyl)-1,4-
Dihydroquinol-4-one 3-carboxylate
(446 mg, 1.2 mmol) was hydrolyzed to form a white solid.
(332 mg, 80% yield); m.p.>280°C; IR (KBr, cm^-1): 1718(s), 1612(s), 1567
(s), 1539(s); NMR (CF₃C.O.₂D, 250MHz): 9.30 (s, 1H),
8.25 (d, 1H, J = 10Hz), 7.65 (d, 2H, J =
10Hz), 7.22 (d, 2H, J=10Hz), 4.70 (d,
3H, J=10Hz), 3.96(s, 3H); MS:C₁₈H₁₃F₂NO._Fouras Calculated value: 345.0812, Actual value: 345.0821 Elemental analysis: C₁₈H₁₃F₂NO._Fouras Calculated value: C, 62.61; H, 3.79; N, 4.06% Actual value: C, 62.43; H, 3.81; N, 3.95% Example 34 6,8-difluoro-7-(4-hydroxyph)
enyl)-1-methyl-1,4-dihydroquino
R-4-one 3-carboxylic acid Following the method of Example 14, 6,8-difluoro-
7-(4-methoxyphenyl)-1-methyl-1,
4-dihydroquinol-4-one 3-carboxylic acid
(202 mg, 0.6 mmol) and boron tribromide
Thylene chloride solution (1M, 5.9ml, 5.9mmol)
was reacted to obtain a crude product as a yellow solid.
Trituration in hot water gave a white solid (126 mg, 65
% yield); m.p.>270℃; NMR (CF₃C.O.₂D, 250MHz): 9.34 (s, 1H),
8.30 (d, 1H, J = 10Hz), 7.58 (d, 2H, J =
10Hz), 7.20 (d, 2H, J=10Hz), 4.73 (d,
3H, J=10Hz); MS:C₁₆H₁₁F₂NO.₂as (parent ion − CO₂): Calculated value: 287.0758, Actual value: 287.0751 Elemental analysis: C₁₇H₁₁F₂NO._Four・0.25H₂as O Calculated value: C, 60.81; H, 3.45; N, 4.17% Actual value: C, 60.46; H, 3.33; N, 4.05% Reference example 1 Ethyl 7-bromo-6,8-difluoro-1-
Allyl-1,4-dihydroquinol-4-one
3-carboxylate Following the method of Example 1D, ethyl 7-bromo-
6,8-difluoro-4-hydroxyquinoline 3
-Carboxylate (5.0 g, 15 mmol), anhydrous
Potassium carbonate (4.16 g, 30 mmol) and bromide
Allyl (5.4 g, 4 ml, 45 mmol) in dimethyl
The 2-propanol was reacted in formamide (50 ml).
Recrystallization from alcohol gave a white solid (4.2 g,
75% yield); m, p.141-143℃; IR (CHCl₃,cm^-1): 1732(s), 1694(s), 1642
(s), 1610 (s), 1546 (m); NMR (CDCl)₃, 250MHz): 8.40 (s, 1H), 8.12
(dd, 1H, J = 10, 4Hz); 6.15−6.00 (m,
1H), 5.35 (d, 1H, J=10Hz), 5.18 (d,
1H, J=20Hz), 5.00-4.86 (m, 2H), 4.40
(q, 2H, J = 7Hz), 1.40 (t, 3H, J = 7
Hz). Elemental analysis: C₁₅H₁₂BrF₂NO.₃as Calculated value: C, 48.43; H, 3.25; N, 3.77; Br,
21.48; F, 10.21% Actual value: C, 48.13; H, 3.28; N, 3.66; Br,
21.15; F, 10.29% Reference example 2 Ethyl 7-bromo-6,8-difluoro-1-
Benzyl-1,4-dihydroquinol-4-o
3-carboxylate Following the method of Example 1D, ethyl 7-bromo-
6,8-difluoro-4-hydroxyquinoline 3
-Carboxylate (5.0 g, 15 mmol), anhydrous
Potassium carbonate (4.2 g, 30 mmol) and Ben
Dilbromide (7.7 g, 5.4 ml, 45 mmol)
React in methylformamide (50ml) 2-
A white solid was obtained after recrystallization from propanol.
(4.4g, 70% yield); m, p.184-186℃; IR (CHCl₃,cm^-1): 1732(s), 1695(s), 1643
(s), 1610 (s), 1548 (m); NMR (CDCl)₃, 250MHz): 8.50 (s, 1H), 8.10
(d, 1H, J=10Hz), 7.45-7.25 (m, 3H),
7.17−7.05 (m, 2H), 5.55 (d, 2H, J=4
Hz), 4.40 (q, 2H, J=7Hz), 1.40 (t, 3H,
J=7Hz). Elemental analysis: C₁₉H₁₄BrF₂NO.₃as Calculated value: C, 54.05; H, 3.34; N, 3.32; Br,
18.90; F, 9.00% Actual value: C, 53.59; H, 3.30; N, 3.24; Br,
18.80; F, 9.10% Example 35 A Ethyl 7-bromo-6,8-difluoro-1
-propyl-1,4-dihydroquinol-4-
On 3-carboxylate Following the method of Example 1D, ethyl 7-bromo-
6,8-difluoro-4-hydroxyquinoline 3
-Carboxylate (5.0 g, 15 mmol), anhydrous
Potassium carbonate (4.16 g, 30 mmol) and 1-bu
Lomopropane (11 g, 8.2 ml, 90 mmol)
React in methylformamide (50ml) 2-
A white solid was obtained after recrystallization from propanol.
(2.7g, 48% yield); m, p.139-140℃; IR (CHCl₃,cm^-1): 1731(s), 1692(s), 1641
(s), 1610 (s); NMR (CDCl)₃, 250MHz): 8.40 (s, 1H), 8.15
(dd, 1H, J = 10, 4Hz), 4.42 (q, 2H, J
=7Hz), 4.35-4.25 (m, 2H), 1.97 (sex
Tetsut, 2H, J=7Hz), 1.42(t, 3H, J=
7Hz). Elemental analysis: C₁₅H₁₄BrF₂NO.₃as Calculated value: C, 48.17; H, 3.77; N, 3.75; Br,
21.37; F.10.16% Actual value: C, 47.86; H, 3.73; N, 3.84; Br,
21.10; F, 10.35% B Ethyl 6,8-difluoro-7-(4-meth
xyphenyl)-1-propyl-1,4-dihy
Droquinol-4-one 3-carboxylate Following the method of Example 2, ethyl 7-bromo-
6,8-difluoro-1-propyl-1,4-di
Hydroquinol-4-one 3-carboxylate
(1.0 g, 2.7 mmol), 1-bromo-4-methoxy
No Sibenzene (1.26g, 0.84ml, 6.75mmol)
Zinc chloride hydrate (1.1 g, 8.1 mmol), t-butyl
Lithium in pentane solution (1.8M, 7.5ml, 13.5ml)
limole) and tetrakis (triphenylphosph)
In) React with palladium (320mg) to produce crude product
The product was obtained as a yellow solid. Acetate on silica gel
Pale yellow due to chromatography using chilled elution.
A colored solid was obtained (360 mg, 73% yield); m.p.126−
128℃; IR (KBr, cm^-1): 1734(s), 1612(s), 1574
(m); NMR (CDCl)₃, 250MHz): 8.45 (s, 1H), 8.15
(dd, 1H, J = 10, 3Hz), 7.42 (d, 2H, J
= 8Hz), 7.05 (d, 2H, J = 8Hz), 4.44 (q,
2H, J=7Hz), 3.92(s, 3H), 3.35−3.25
(m, 2H), 2.00−1.85 (m, 2H), 1.45 (t,
3H, J = 7Hz), 1.00 (t, 3H, J = 7Hz). Elemental analysis: C_{twenty two}H_{twenty one}F₂NO._Four・0.25H₂as O Calculated value: C, 65.10; H, 5.34; N, 3.45% Actual value: C, 65.22; H, 5.24; N, 3.38% C 6,8-difluoro-7-(4-methoxyf
enyl)-1-propyl-1,4-dihydroxy
Nol-4-one 3-carboxylic acid Following the method of Example 13B, ethyl 6,8-diphthyl
fluoro-7-(4-methoxyphenyl)-1-pro
Pyr-1,4-dihydroquinol-4-one 3-
Hydrogenated carboxylate (245 mg, 0.6 mmol)
Decomposition gave a white solid (154 mg, 68% yield);
m, p.272−274℃; IR (KBr, cm^-1): 1722(s), 1612(s); NMR (1% DMSO-d₆/CF₃C.O.₂D，250M
Hz): 9.34 (s, 1H), 8.30 (d, 1H, J=8
Hz), 7.62 (d, 2H, J=8Hz), 7.22 (d, 2H,
J = 8Hz), 5.10-4.88 (m, 2H), 3.96 (s,
3H), 2.25-2.10 (m, 2H), 1.12 (t, 3H, J
=7Hz). MS:C₂₀H₁₇F₂NO._Fouras Calculated value: 373.1126, Actual value: 373.1146 Elemental analysis: C₂₀H₁₇F₂NO._Fouras Calculated value: C, 64.34; H, 4.59; N, 3.75% Actual value: C, 63.91; H, 4.49; N, 3.67% Example 38 6,8-difluoro-7-(4-hydroxyph)
enyl)-1-propyl-1,4-dihydroxy
Nol-4-one 3-carboxylic acid Following the method of Example 14, 6,8-difluoro-
7-(4-methoxyphenyl)-1-propyl-
1,4-dihydroquinol-4-one 3-carbo
phosphoric acid (103 mg, 0.28 mmol) and boron tribromide
Plain methylene chloride solution (1M, 2.8ml, 2.8ml)
The crude product is a yellow solid.
I got it. Grind in boiling water to remove white solids.
Obtained (98 mg, 98% yield); m, p. 262-264°C; IR (KBr, cm^-1): 1721 (s), 1614 (m), 1561
(m); NMR (1% DMSO-d₆/CF₃COD₂，250M
Hz): 9.35 (s, 1H), 8.30 (d, 1H, J=8
Hz), 7.62 (d, 2H, J=8Hz), 7.20 (d, 2H,
J = 8Hz), 5.10-4.95 (m, 2H), 3.98 (s,
3H), 2.20-2.10 (m, 2H), 1.60-1.40 (m,
2H), 1.05 (t, 3H, J = 7Hz). MS:C₁₉H₁₅F₂NO._Fouras Calculated value: 359.0980, Actual value: 359.0969 Example 39 A Ethyl 7-bromo. 6,8-difluoro-1
-butyl-1,4-dihydroquinol-4-o
3-carboxylate Ethyl 7-bromo-6, according to the method of Example 1D
8-difluoro-4-hydroxyquinoline 3-ka
Ruboxylate (5.0 g, 15 mmol), carbonic anhydride
Potassium (4.2 g, 30 mmol) and 1-bro
Mobutan (18.5g, 14.4ml, 135mmol)
Reacted in methylformamide to produce 2-propyl
A white solid was obtained by recrystallization from alcohol (3.1
g, 53% yield); m, p.140-1641℃; IR (CHCl₃,cm^-1): 1731(s), 1629(s), 141
(s), 1610 (s), 1547 (m), 1480 (s); NMR (CDCl)₃, 250MHz): 8.40 (s, 1H), 8.15
(dd, 1H, J = 10, 4Hz), 4.42 (q, 2H, J
=7Hz), 4.40-4.25 (m, 2H), 1.95-1.85 (m,
2H), 1.65-1.40 (m, 2H), 1.41 (t, 3H, J
= 7Hz), 1.00 (t, 3H, J = 7Hz). Elemental analysis: C₁₆H₁₆BrF₂NO.₃as Calculated value: C, 49.53; H, 4.16; N, 3.61; Br,
20.60; F, 9.79% Actual value: C, 49.65; H, 4.12; N, 3.56; Br,
20.59; F, 10.21% B Ethyl 6,8-difluoro-7-(4-meth
xyphenyl)-1-butyl-1,4-dihyde
quinol-4-one 3-carboxylate Following the method of Example 2, ethyl 7-bromo-
6,8-difluoro-1-butyl-1,4-dihydrogen
Droquinol-4-one 3-carboxylate
(1 g, 2.6 mmol), 1-bromo-4-methoxy
Sibenzene (1.22g, 0.82ml, 6.6mmol), no
Zinc chloride hydrate (1.1 g, 8.1 mmol), t-butyl
Lithium in pentane solution (1.8M, 7.3ml, 13.1ml)
limole) and tetrakis((triphenylphos)
(Fin) Reacted with palladium (300mg) and crude
The product was obtained as a yellow solid, which was further purified.
I used it without any problems. C 6,8-difluoro-7-(4-methoxyf
enyl)-1-butyl-1,4-dihydroquino
R-4-one 3-carboxylic acid Following the method of Example 13B, ethyl 6,8-diphthyl
fluoro-7-(4-methoxyphenyl)-1-buty
Ru-1,4-dihydroquinol-4-one 3-ka
The ruboxylate was hydrolyzed to obtain a white solid.
(134mg, 13% yield); m.p.248−249℃; IR (KBr, cm^-1): 1721 (s), 1641 (m) 1561
(m), 1538 (m); NMR (1% DMSO-d₆/CF₃C.O.₂D，250M
Hz): 9.35 (s, 1H), 8.30 (d, 1H, J=8
Hz), 7.62 (d, 2H, J=8Hz), 7.20 (d, 2H,
J = 8Hz), 5.10-4.95 (m, 2H), 3.98 (s,
33H), 2.20-2.10 (m, 2H), 1.60-1.40 (m,
2H), 1.05 (t, 3H, J=7Hz); MS: 387 (parent ion peak), 343 (reference peak). Elemental analysis: C_{twenty one}H₁₉F₂NO._Four・0.5H₂as O Calculated value: C, 63.63; H, 5.09; N, 3.53% Actual value: C, 63.73; H, 4.79; N, 3.46% Example 40 6,8-difluoro-7-(4-hydroxyph)
enyl)-1-butyl-1,4-dihydroquino
R-4-one 3-carboxylic acid Following the method of Example 14, 6,8-difluoro-
7-(4-methoxyphenyl)-1-butyl-1,
4-dihydroquinol-4-one 3-carboxylic acid
(91 mg, 0.24 mmol) and boron tribromide solution
(1M, 2.4ml, 2.4mmol)
The product was obtained as a yellow solid. Grinding in boiling water
A white solid is obtained by crushing, filtering and drying under vacuum.
Obtained (40 mg, 45% yield); NMR (5% DMSO-d₆/CF₃C.O.₂D，250M
Hz): 9.46 (s, 1H), 8.35 (d, H, J = 10Hz),
7.56 (d, 2H, J = 10Hz), 7.20 (d, 2H, J =
10Hz), 5.10-4.95 (m, 1H), 2.25-205 (m,
2H), 1.75-1.55 (m, 2H), 1.10 (t, 3H, J
=7Hz); MS:C₂₀H₁₇F₂NO._Fouras Calculated value: 373.1126, Actual value: 373.1082 Elemental analysis: C₂₀H₁₇F₂NO._Four・0.75H₂as O Calculated value: C, 62.09; H, 4.82; N, 3.62% Actual value: C, 62.15; H, 4.82; N, 3.85% Example 41 A Ethyl 6,8-difluoro-7-(4-chloro
Rosulfonylphenyl)-1-ethyl-1,4
-dihydroquinol-4-one 3-carboxy
rate Following the method of Example 10A, ethyl 6,8-diphthyl
fluoro-7-phenyl-1-ethyl-1,4-di
Hydroquinol-4-one 3-carboxylate
(0.55g, 1.53mmol) and chlorosulfone
React acid (6 ml) in methylene chloride (10 ml).
A pale yellow oil (0.7 g) was obtained, which was further purified.
I used it without any problems. B Ethyl 6,8-difluoro-7-(4-amino)
Nosulfonylphenyl)-1-ethyl-1,4
-dihydroquinol-4-one 3-carboxy
rate Ethyl 6,8-difluoro-7-(4-chloro
-sulfonylphenyl)-1-ethyl-1,4-
Dihydroquinol-4-one 3-carboxylate
(0.7g) in anhydrous tetrahydrofuran (10ml)
The resulting solution was cooled to -78°C. Ann
Monia (5 ml) was coagulated into the reaction mixture with stirring.
Shrunk. The reaction mixture was warmed to room temperature and stirred for 16 hours.
Stirred. The solvent was distilled off under vacuum, water then ether
The crude product was obtained by trituration in a medium. Dry under vacuum to pale
A yellow solid was obtained (0.6 g, 90% yield);
250℃; NMR (3% DMSO-d₆/CF₃C.O.₂D，250M
Hz): 9.38 (s, 1H), 8.40 (d, 1H, J8Hz),
8.20 (d, 2H, J=8Hz), 7.95−7.85 (m,
2H), 7.72 (d, 2H, J=8Hz), 5.20−5.05
(m, 2H) 4.72 (q, 4H, J=7Hz), 1.80 (t,
3H, J=7Hz), 1.55 (t, 3H, J=7Hz); MS:C₂₀H₁₈F₂N₂O_Fiveas S Calculated value: 436.0909, Actual value: 436.0912 C 6,8-difluoro-7-(4-aminosul
Honylphenyl)-1-ethyl-1,4-dihy
Doroquinol-4-one 3-carboxylic acid Following the method of Example 10C, ethyl 6,8-diphthyl
fluoro-7-(4-aminosulfonylphenyl)-
1-ethyl-1,4-dihydroquinol-4-o
3-carboxylate (0.32 g, 0.73 mmol)
) and 1N sodium hydroxide solution in ethanol.
(4ml) was reacted to obtain a white solid (0.25ml).
g, 84% yield); m, p.>250°C; NMR (1% DMSO-d₆/CF₃C.O.₂D，250M
Hz): 9.45 (s, 1H), 8.40 (d, 1H, J=8
Hz), 8.24 (d, 2H, J=8Hz), 8.00−7.85
(m, 2H), 5.25-5.00 (m, 2H), 1.82 (t,
3H, J=7Hz). MS:C₁₈H₁₄F₂N₂O_Fiveas S Calculated value: 408.0580, Actual value: 408.0560 Example 42 Additionally, the following compounds were synthesized:

【table】

[Table] Example 43 A 2,4-difluoro-3-bromo-1-nitrobenzene A solution of 1,3-difluoro-2-bromobenzene (23.5 g, 112 mmol) in concentrated sulfuric acid (48 ml) was stirred vigorously at room temperature. do. Concentrated nitric acid (70%, 8 ml) was added dropwise so that the internal temperature of the reaction mixture did not exceed 55°C. The reaction was then stirred for 15 min and placed on ice (300 ml).
Poured on top. The aqueous mixture was extracted three times with methylene chloride. The combined organic layers were washed three times with saturated sodium bicarbonate solution, dried over magnesium sulfate, and filtered. The solvent was removed under vacuum to give a yellow solid. Recrystallization from isopropyl ether gave a white solid (28.2 g, 97% yield); m, p.50-
51.5℃. NMR (CDCl ₃ , 60MHz): 8.4-7.9 (m, 1H), 7.4
−7.0 (m, 1H). Elemental analysis: as C ₆ H ₂ BrF ₂ NO ₂ Calculated values: C, 30.28; H, 0.85; N, 5.89; Br,
33.57; F, 15.96% Actual value: C, 30.34; H, 0.98; N, 5.81; Br,
33.81; F, 16.04% B 3-bromo-4-fluoro-2-hydroxy-1-nitrobenzene A solution of 3-bromo-2,4-difluoro-1-nitrobenzene (10.5 g, 44 mmol) in dimethyl sulfoxide (85 ml) Stir at room temperature. Potassium hydroxide (14.1 g, 251 mmol) in water (21 ml)
The solution was added dropwise over 15 minutes. The black reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then poured into water (200 ml) and extracted three times with ether (100 ml). The aqueous layer was acidified with concentrated hydrochloric acid and extracted three times with ether (100ml). The combined organic layers were dried with magnesium sulfate and filtered. Removal of the solvent under vacuum gave a yellow solid (9.7 g, 93% yield). Analytical samples were obtained by recrystallization from isopropyl ether: mp 65-66°C. NMR (CDCl ₃ , 60MHz): 8.1 (dd, 1H, J = 10.5
Hz), 6.8 (dd, 1H, J = 10.8Hz). Elemental analysis: as C ₆ H ₃ BrFNO ₃ Calculated value: C, 3.054; H, 1.30; N, 5.94; Br,
33.86; F, 8.05% Actual value: C, 30.52; H, 1.27; N, 5.70; Br,
33.56; F, 7.96% C 1-(2-bromo-3-fluoro-6-nitrophenoxy)-propan-2-one chloroacetone (3.8 g, 3.3 ml, 41 mmol)
3-bromo-4-fluoro-2-hydroxy-
The mixture was added dropwise to a solution of 1-nitrobenzene (4.3 g, 18.2 mmol) in acetone (54 ml) at room temperature with stirring. Potassium carbonate (5.8 g, 42 mmol) and potassium iodide (6.0 g, 36.4 mmol) were added and the reaction mixture was heated to reflux for 2 hours. Cool the reaction mixture to room temperature and add water (100ml)
and extracted three times with acetic acid and ethyl (150 ml). The combined organic layers were dried with magnesium sulfate, decolorized with activated carbon, and passed through diatomaceous earth. The solvent was removed under vacuum to give a dark brown oil. Silica gel chromatography was performed using ethyl acetate-hexane (1:1) and the solvent was removed in vacuo to obtain a dark brown liquid (Rf = 0.67, 3.5 g,
66% yield): NMR ( _CDCl3 , 60MHz): 8.1 (dd, 1H, J=10.6
Hz), 7.4 (dd, 1H, J=10.8Hz), 4.6 (s,
2H), 2.3(s, 3H). D 8-Bromo-7-fluoro-3-methyl-
2,3-dihydro-1,4-benzoxazine Raney nickel (0.5 g) in absolute ethanol (10 ml) was dissolved in 1-(2-bromo-4-fluoro-6-nitrophenoxy)-propane-2-
(21 g, 7.2 mmol) in absolute ethanol (200 ml). The reaction mixture was placed in a Parr apparatus and shaken under a hydrogen atmosphere (15 psi) for 1 hour. The reaction mixture was passed through diatomaceous earth. The solvent was removed under vacuum to give a dark brown oil (1.5 g, 85% yield): NMR ( _CDCl3 , 60MHz): 6.7-6.5 (m, 2H), 4.5
-3.7 (m, 3H), 1.3 (d, 3H, J = 7Hz). Elemental analysis: _{as C9H9BrFNO} Calculated value: C, 43.93; H, 3.69; N, 5.69% Actual value: C, 43.96; H, 3.89; N, 5.14% E Ethyl 10-bromo-9-fluoro-3 -Methyl-7-oxo-2,3-dihydro-(7H)-
Pyrido-(1,2,3-de)-1,4-benzoxazine-6-carboxylate 8-bromo-7-fluoro-3-methyl-2,
3-dihydro-1,4-benzoxazine (3g,
12.2 mmol) and diethyl ethoxy-methylene malonate (2.8 g, 2.6 ml, 12.9 mmol) under nitrogen atmosphere for 1 hour and then under reduced pressure (5 psi).
Heated to 140°C for 0.5 hours. Crude product, diethyl 2
-(8-bromo-7-fluoro-3-methyl-2,
3-dihydro-1,4-benzoxazinyl)methylenepropane-1,3-dioate was used without further purification. The above product was stirred with polyphosphoric acid ester (10 g) at 140° C. for 1 hour under nitrogen atmosphere. The reaction mixture was then poured into water (200ml). The aqueous mixture is made basic (PH=10 with saturated sodium hydroxide solution)
(using test paper) and 3 degrees chloroform (200ml)
Extracted with. The combined organic layers were dried with magnesium sulfate, decolorized with activated carbon and passed through diatomaceous earth. The solvent was removed under vacuum to obtain a solid. The solids were dissolved in saturated sodium bicarbonate solution (100
ml) and stirred for 30 minutes. The suspension was extracted three times with chloroform and the combined organic layers were dried over magnesium sulfate. The solvent was removed under vacuum to obtain a solid. Trituration in ether, filtration and drying under vacuum gave a white solid (2.4 g, 53% yield): m.
p.＞250℃. NMR (CDCl ₃ , 250MHz): 8.35 (s, 1H), 7.75
(d, 1H, J=8Hz), 4.60−4.30 (m, 3H),
4.48 (q, 2H, J = 7Hz), 1.60 (d, 3H, J =
7Hz), 1.40 (t, 3H, J = 7Hz). Elemental analysis: as C ₁₅ H ₁₃ BrFNO ₄ Calculated values: C, 48.67; H, 3.54; N, 3.78;
Br21.59; F, 5.13% Actual value: C, 48.44; H, 3.56; N, 3.66; Br,
21.60; F, 5.25% F 10-bromo-9-fluoro-3-methyl-7
-oxo-2,3-dihydro-(7H)-pyrido-(1,2,3-de)-1,4-benzoxazine-6-carboxylic acid ethyl 10-bromo-9-fluoro-3-methyl-7- Oxo-2,3-dihydro-(7H)-pyrido-(1,2,3-de)-1,4-benzoxazine-6-carboxylate (0.2 g, 0.54 mmol)
and 3N hydrochloric acid solution (15ml) was heated to 100°C with stirring for 17 hours. The reaction mixture was diluted twice with water and filtered. The white solid collected was washed with water, triturated in acetone and filtered.
Drying under vacuum gave a white solid (142 mg, 77%
Yield): mp250℃. NMR (5%DMSO- _d6 / _CF3CO2D , _250M
Hz): 9.12 (s, 1H), 7.80 (d, 1H, J=8
Hz), 5.10-5.00 (m, 1H), 4.80-4.70 (m,
1H), 4.60-4.50 (m, 1H), 1.52 (d, 3H, J
=7Hz). Elemental analysis: as C ₁₃ H ₉ BrFNO ₄ Calculated value: C, 45.64; H, 2.65; N, 4.09% Actual value: C, 45.70; H, 2.64; N, 3.90% G Ethyl 9-fluoro-10-phenyl- 3-Methyl-7-oxo-2,3-dihydro-(7H)
-Pyrido-(1,2,3-de)-1,4-benzoxazine-6-carboxylate Dry an ether-benzene solution of phenyllithium (2.7M) [(3:7), 1.5ml, 4mmol] The resulting solution was added to tetrahydrofuran (10 ml) and cooled to -78°C with stirring under nitrogen atmosphere. A solution of freshly molten zinc chloride (0.54 g, 4 mmol) in dry tetrahydrofuran (10 ml) was added to
It took more than a minute to drip. The clear, colorless solution was warmed to -30°C over 20 minutes. amino9-fluoro-10-bromo-3-methyl-7-oxo-2,
3-dihydro-(7H)-pyrido-(1,2,3-
De)-1,4-benzoxazine-6-carboxylate (1.0 g, 2.7 mmol) was added in one portion;
then dichlorobis(triphenylphosphine)
Nickel (0.13 g, 0.2 mmol) was added in one portion. The reaction mixture was gradually warmed to room temperature and stirred for 24 hours. Add dark brown mixture to 1N hydrochloric acid solution (100ml)
and the aqueous mixture was stirred for 15 minutes. Extracted three times with chloroform (50 ml), the combined organic layers were dried over magnesium sulfate, treated with decolorizing charcoal, and passed through diatomaceous earth to yield a yellow liquid. The solvent was removed under vacuum to give a bright yellow solid. Trituration in ether and drying under vacuum gave a pale yellow solid (0.67 g, 46% yield): mp4-270
−272℃. NMR (CDCl ₃ , 250MHz): 8.42 (s, 1H), 7.85
(d, 1H, J=10Hz), 7.55-7.40 (m, 5H),
4.42 (q, 2H, J=7Hz), 4.50−4.35 (m,
3H), 1.62 (d, 3H, J=8Hz), 1.45 (t,
3H, J=7Hz). MS: C ₂₁ H ₁₈ FNO ₄ Calculated value: 367.1223, Actual value: 367.1179 H 9-Fluoro-10-phenyl-3-methyl-
7-oxo-(7H)-2,3-dihydro-(1,
2,3-de)-1,4-benzoxazine 6-carboxylic acid (R ₁ = H, R ₃ = phenyl and R ₂ and Y together form -O-CH ₂ -CH ₂ -) Ethyl 9-fluoro -10-phenyl-3-methyl-7-oxo-(7H)-2,3-dihydro-
(1,2,3-de)-1,4-benzoxazine-6
-carboxylate (420 mg, 1.1 mmol)
1N hydrochloric acid solution (10ml) and ethanol (10ml)
suspended in. The suspension was heated to 90°C with stirring. The suspension was cooled to room temperature and filtered. The collected solids were washed with water followed by methanol. Drying under vacuum gave a pale yellow solid (0.3 g, 80% yield): mp 250°C. NMR (1%DMSO- _d6 / _CF3CO2D , _250M
Hz): 8.92 (s, 1H), 7.64 (d, 1H, J=10
Hz), 7.30-7.10 (m, 5H), 4.85-4.70 (m,
1H), 4.35-4.15 (m, 2H), 1.42 (d, 3H, J
=8Hz). MS: As C ₁₉ H ₁₄ FNO ₄ Calculated value: 339.0907, Actual value: 339.0911 Example 44 A Ethyl 9-fluoro-10-(4-chlorosulfonylphenyl)-3-methyl-7-oxo-
2,3-dihydro-(7H)-pyrido-(1,2,
3-de)-1,4-benzoxazine-6-carboxylate Ethyl 9-fluoro-10-phenyl-3-methyl-7-oxo-2,3-dihydro-(7H)-pyrido-(1,2,3 A suspension of -de)-1,4-benzoxazine-6-carboxylate (0.4 mg, 1.2 mmol) in dichloromethane (15 ml) was cooled to 0°C with stirring. Chlorosulfonic acid (5ml)
was added dropwise over 5 minutes. Bring the dark solution to 0 °C for 15 min.
Stir and gradually warm to room temperature over 1.5 hours. The reaction mixture was poured into ice water with stirring. Extraction was carried out three times with chloroform, the combined organic layers were dried over magnesium sulfate, and the solvent was then evaporated in vacuo to yield a yellow oil (0.5 g), which was used without further purification. B Ethyl 9-fluoro-10-(4-aminosulfonylphenyl)-3-methyl-7-oxo-
2,3-dihydro-(7H)-pyrido-(1,2,
3-de)-1,4-benzoxazine-6-carboxylate ethyl 9-fluoro-10-(4-chlorosulfonylphenyl)-3-methyl-7-oxo-2,
3-dihydro-(7H)-pyrido-(1,2,3-
De)-1,4-benzoxazine-6-carboxylate (0.5 g) was dissolved in dry tetrahydrofuran (80 g).
ml) and the resulting solution was heated to -78 ml with stirring.
Cooled to ℃. Ammonia (5
ml) was condensed and the yellow suspension was gradually warmed to room temperature over 16 hours. Distill the solvent under vacuum,
The residue was triturated in water and filtered. Drying under vacuum gave a solid (0.3 g, 56% yield); m, p.>250
℃. NMR (DMSO-d ₆ , 250MHz): 8.74 (s, 1H),
7.96 (d, 2H, J = 10Hz), 7.74 (d, 2H, J =
10Hz), 7.60 (d, 1H, J=10Hz), 7.50 (s,
2H), 4.90-4.75 (m, 1H), 4.55-4.45 (m,
2H), 4.25 (q, 2H, J=7Hz), 1.45 (d,
3H, J = 7Hz), 1.30 (t, 3H, J = 7Hz). Elemental analysis: _{as C21H19FN2O6S Calculated value} : C, 56.50; H, 4.29; _N , 6.27% Actual value: C, 56.13; H, 4.52; N, 6.18% C9-Fluoro-10- (4-Aminosulfonylphenyl)-3-methyl-7-oxo-2,3
-dihydro-(7H)-pyrido-(1,2,3-
De) Ethyl 1,4-benzoxazine-6-carboxylate 9-fluoro-10-(4-aminosulfonylphenyl)-3-methyl-7-oxo-2,
3-dihydro-(7H)-pyrido-(1,2,3-
A mixture of de)-1,4-benzoxazine-6-carboxylate (250 mg, 0.6 mmol), 1N sodium hydroxide solution (7 ml) and ethanol (7 ml) is heated to 90° C. for 30 minutes with stirring. The reaction mixture was cooled to room temperature and concentrated under vacuum. The milky suspension was neutralized with 1N hydrochloric acid solution. The precipitate was collected and washed with water. Drying under vacuum gave a white powder (160 mg, 68% yield): m, p. 250°C. NMR (1%DMSO- _d6 / _CF3CO2D , _250M
Hz): 8.95 (s, 1H), 7.74 (d, 2H, J=10
Hz), 7.65 (d, 1H, J=10Hz), 7.37 (d, 2H,
J=10Hz), 4.85-4.70 (m, 1H), 4.30-4.15
(m, 2H), 1.40 (d, 3H, J=7Hz). Elemental analysis: _{C19H15FN2O6 ・ 2H2O} Calculated value: C, _50.21 ; H, 4.21; N, 6.16% Actual value: C _, 50.50; H, 3.55; N, 6.25%

Claims (1)

[Claims] 1 formula (In the formula, R ₁ is hydrogen, alkyl having 1 to 6 carbon atoms,
benzyl or a pharmaceutically suitable cation; _R2 is hydrogen or fluoro; Y is alkyl, haloalkyl or polyhaloalkyl having 1 to 3 carbon atoms; hydroxyethyl;
Cyclopropyl; Vinyl; Allyl; Phenyl; 4
-hydroxyphenyl; or 4-fluorophenyl; R′ ₀ is hydrogen, alkylsulfinyl having 1 to 4 carbon atoms, alkylsulfonyl having 1 to 4 carbon atoms, hydroxy, alkoxy having 1 to 4 carbon atoms, Carbon number 1~
3 hydroxyalkyl, amino, carbon number 1-3
aminoalkyl, formamide, carbon number 2-3
alkanoylamino, aminosulfonyl, nitro, formyl or N-(N',N'-dimethylformamidino); R″ ₀ is hydrogen, 3-hydroxy or 3-chloro).