This invention relates to processes for producing a 7-isoindoline-quinolonecarboxylic acid derivative represented by the general formula [1] and its intermediate as well as a salt of 7-isoindoline-quinolonecarboxylic acid derivative represented by the general formula [1], its hydrate and a composition comprising the same as an active ingredient: 
wherein R1 represents a hydrogen atom or a carboxyl-protecting group; R2 represents a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, aryl or heterocyclic group; R3 represents at least one group selected from hydrogen atom, halogen atoms, substituted or unsubstituted alkyl, alkenyl, cycloalkyl, aryl, alkoxy or alkylthio groups, nitro group, cyano group, acyl groups, protected or unprotected hydroxyl groups and protected or unprotected or substituted or unsubstituted amino groups; R4 represents at least one group selected from hydrogen atom, halogen atoms, substituted or unsubstituted alkyl, alkenyl, cycloalkyl, aralkyl, aryl, alkoxy or alkylthio groups, protected or unprotected hydroxyl or imino groups, protected or unprotected or substituted or unsubstituted amino groups, alkylidene groups, oxo group and groups each forming a cycloalkane ring with the carbon atom to which R4 bonds; R5 represents a hydrogen atom, an amino-protecting group or a substituted or unsubstituted alkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group; R6 represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, alkoxy or alkylthio group, a protected or unprotected hydroxyl or amino group or a nitro group; and A represents CH or Cxe2x80x94R7 in which R7 represents a halogen atom, a substituted or unsubstituted alkyl, alkoxy or alkylthio group or a protected or unprotected hydroxyl group.
As the process for producing a compound of the general formula [1], there has been known the process described in WO97/29102. That is to say, said publication describes that a compound of the general formula [1] can be produced by subjecting a 5-halogenoisoindoline derivative represented by the following general formula [4] or its salt: 
wherein R3, R4 and R5 have the same meanings as mentioned above and X1 represents a halogen atom, to lithiation or Grignard reaction and thereafter to reaction with a trialkyl borate to form an isoindoline-5-boronic acid derivative represented by the following general formula [2c] or its salt: 
wherein R3, R4 and R5 have the same meanings as mentioned above and R11 represents a hydrogen atom or an alkyl group; and subsequently reacting the isoindoline-5-boronic acid derivative or its salt with a 7-halogenoquinolonecarboxylic acid represented by the following general formula [3b]: 
wherein R1, R2, R6 and A have the same meanings as mentioned above and X3 represents a halogen atom, in the presence of a palladium complex such as bis(triphenylphosphine)-palladium(II) chloride, tetrakis(triphenylphosphine)-palladium(0) or the like.
Among the compounds of the general formula [1], (R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinoline-carboxylic acid represented by the formula: 
(referred to hereinafter as T-3811) is a compound excellent in activity against Gram-positive and Gram-negative bacteria and the development of a process for industrially producing the same has been desired.
Moreover, T-3811 is low in solubility in the vicinity of neutral, so that the enhancement of solubility at a physiologically acceptable pH has been desired.
In order to develop a process for industrially producing a 7-isoindoline-quinolonecarboxylic acid derivative of the general formula [1] including T-3811, the present inventors have diligently made research to find consequently that a coupling reaction between an isoindoline-5-boronic acid derivative represented by the following general formula [2]: 
wherein R3, R4 and R5 have the same meanings as mentioned above and R8 and R9 represent hydrogen atoms or lower alkyl groups or form a ring comprising the boron atom when taken together, and a 7-leaving group-substituted quinolone-carboxylic acid represented by the following general formula [3]: 
wherein R1, R2, R6 and A have the same meanings as mentioned above and X2 represents a leaving group, can be easily carried out in the presence of metallic palladium.
Furthermore, it has been found that an isoindoline-5-boronic acid derivative represented by the following general formula [2a]: 
wherein R3, R4 and R5 have the same meanings as mentioned above and Z represents an alkylene group can easily be obtained not by the conventional borodation through lithiation or Grignard reaction but by the reaction of a 5-halogenoisoindoline derivative represented by the following general formula [4]: 
wherein R3, R4, R5 and X1 have the same meanings as mentioned above, with a dialkoxyborane or an alkoxydiborane in the presence of a palladium catalyst, and further found that the compound of the general formula [2a] can be applied, without being isolated, to the so-called one-pot reaction by which the compound of the general formula [3] is reacted to produce a 7-isoindoline-quinolonecarboxylic acid derivative represented by the general formula [1].
Also, the present inventors have found that a 1-alkylisoindoline-5-boronic acid derivative represented by the following general formula [2b]: 
wherein R4a represents an alkyl group and R5, R8 and R9 have the same meanings as mentioned above is an excellent intermediate for producing a 7-isoindoline-quinolone-carboxylic acid derivative represented by the following general formula [1a]: 
wherein R4a, R1, R2, R5, R6 and A have the same meanings as mentioned above among the compounds of the general formula [1].
Moreover, it has been found that a 1-alkyl-5-halogenoisoindoline derivative represented by the following general formula [4a]: 
wherein R4a, R5 and X1 have the same meanings as mentioned above, can be produced by using a 4-halogenobenzylamine derivative as the starting material.
Furthermore, it has been found that as the process for producing a 7-bromo-quinolonecarboxylic acid derivative represented by the following general formula [3a] which is a useful intermediate for producing T-3811: 
wherein R1b represents a carboxyl-protecting group; R7a represents a substituted or unsubstituted alkyl group; and R2a represents a substituted or unsubstituted alkyl, cycloalkyl, aryl or heterocyclic group, a process in which a 2,4-dibromo-3-hydroxybenzoic acid ester is used as the starting material and which is through various intermediates as mentioned hereinafter is an excellent industrial production process.
As mentioned above, the present inventors have diligently made research on 7-isoindoline-quinolone-carboxylic acid derivatives represented by the general formula [1] including T-3811 and intermediates for producing the same and have accomplished this invention.
In addition, the present inventors have examined various salts of T-3811 which have never been known, and have consequently found that among them, methanesulfonate of T-3811 is much higher in solubility at a physiologically acceptable pH than the other salts of T-3811 and further that T-3811 methanesulfonate hydrate has no polymorphism and is good in stability against humidity, and hence, it has a very high usefulness as a composition, particularly as a starting material for preparation, whereby this invention has been accomplished.
In the present specification, unless otherwise specified, the term xe2x80x9chalogen atomxe2x80x9d means fluorine atom, chlorine atom, bromine atom or iodine atom; the term xe2x80x9calkyl groupxe2x80x9d means a straight or branched chain C1-10 alkyl group, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl or the like; the term xe2x80x9calkenyl groupxe2x80x9d means a straight or branched chain C2-10 alkenyl group, for example, vinyl, allyl, isopropenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl or the like; the term xe2x80x9calkylidene groupxe2x80x9d means a straight or branched chain C1-10 alkylidene group, for example, methylene, ethylidene, propylidene, isopropylidene, butylidene, hexylidene, octylidene or the like; the term xe2x80x9ccycloalkyl groupxe2x80x9d means a C3-6 cycloalkyl group, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the like; the term xe2x80x9ccycloalkane ringxe2x80x9d means a C3-6 cycloalkane ring, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane or the like; the term xe2x80x9calkylene groupxe2x80x9d means a straight or branched chain C1-10 alkylene group, for example, ethylene, trimethylene, tetramethylene, 1,2-dimethylethylene, 1,3-dimethyltrimethylene, 1,1,2,2-tetramethylethylene or the like; the term xe2x80x9calkoxy groupxe2x80x9d means a straight or branched chain C1-10 alkoxy group, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy or the like; the term xe2x80x9calkoxycarbonyl groupxe2x80x9d means an alkoxy-COxe2x80x94 group (in which the alkoxy represents the above-mentioned straight or branched chain C1-10 alkoxy group), for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl or the like; the term xe2x80x9calkylamino groupxe2x80x9d means a straight or branched chain C1-10 alkyl group-substituted amino group, for example, methylamino, ethylamino, propylamino, butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, methylethylamino, dipropylamino, dibutylamino, dipentylamino or the like; the term xe2x80x9calkylthio groupxe2x80x9d means a straight or branched chain C1-10 alkylthio group, for example, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio, heptylthio, octylthio or the like; the term xe2x80x9calkylsulfonyl groupxe2x80x9d means a straight or branched C1-10 alkylsulfonyl group, for example, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropyl-sulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, heptylsulfonyl, octylsulfonyl or the like; the term xe2x80x9cacyl groupxe2x80x9d means, for example, a formyl group, a straight or branched chain C2-5 alkanoyl group such as acetyl, ethylcarbonyl or the like or an aroyl group such as benzoyl, naphthylcarbonyl or the like; the term xe2x80x9caryl groupxe2x80x9d means, for example, a phenyl or naphthyl group; the term xe2x80x9carylsulfonyl groupxe2x80x9d means, for example, a phenylsulfonyl or naphthylsulfonyl group; the term xe2x80x9caralkyl groupxe2x80x9d means, for example, a benzyl, phenethyl, diphenylmethyl or triphenylmethyl group; the term xe2x80x9cheterocyclic groupxe2x80x9d means a 4-membered, 5-membered or 6-membered ring containing at least one hetero atom selected from oxygen atom, nitrogen atom and sulfur atom as the hetero atom forming the ring or a condensed ring thereof, for example, an oxetanyl, thietanyl, azetidinyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyrrolidinyl, benzofuranyl, benzothiazolyl, pyridyl, quinolyl, pyrimidinyl or morpholinyl group.
Moreover, in the present specification, the term xe2x80x9clowerxe2x80x9d means 1 to 5 carbon atoms, provided that the term xe2x80x9clowerxe2x80x9d in the term xe2x80x9clower alkenylxe2x80x9d means 2 to 5 carbon atoms.
The protecting groups for amino group, lower alkylamino group and imino group include all conventional groups usable as amino-protecting groups, and there are mentioned, for example, acyl groups such as trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, o-bromobenzyloxycarbonyl, (mono-, di-, tri-)chloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-amyloxycarbonyl, tert-butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leucyl, 1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl, pivaloyl and the like; ar-lower alkyl groups such as benzyl, diphenylmethyl, trityl and the like; arylthio groups such as 2-nitrophenylthio, 2,4-dinitrophenylthio and the like; alkyl- or aryl-sulfonyl groups such as methanesulfonyl, p-toluenesulfonyl and the like; di-lower alkylamino-lower alkylidene groups such as N,N-dimethylaminomethylene and the like; ar-lower alkylidene groups such as benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthylmethylene and the like; nitrogen-containing heterocyclic alkylidene groups such as 3-hydroxy-4-pyridylmethylene and the like; cycloalkylidene groups such as cyclohexylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, 3,3-dimethyl-5-oxycyclohexylidene and the like; diaryl- or di-ar-lower alkyl-phosphoryl groups such as diphenylphosphoryl, dibenzylphosphoryl and the like; oxygen-containing heterocyclic alkyl groups such as 5-methyl-2-oxo-2H-1,3-dioxol-4-yl-methyl and the like; substituted silyl groups such as trimethylsilyl and the like; etc.
The protecting groups for the carboxyl group include all conventional groups usable as carboxyl-protecting groups and there are mentioned, for example, lower alkyl groups such as methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, tert-butyl and the like; aryl groups such as phenyl, naphthyl and the like; ar-lower alkyl groups such as benzyl, diphenylmethyl, trityl, p-nitrobenzyl, p-methoxybenzyl, bis(p-methoxyphenyl)methyl and the like; acyl-lower alkyl groups such as acetylmethyl, benzoylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl, p-methanesulfonylbenzoylmethyl and the like; oxygen-containing heterocyclic groups such as 2-tetra-hydropyranyl, 2-tetrahydrofuranyl and the like; halogeno-lower alkyl groups such as 2,2,2-trichloroethyl and the like; lower alkylsilyl-lower alkyl groups such as 2-(trimethylsilyl)ethyl and the like; acyloxy-lower alkyl groups such as acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl and the like; nitrogen-containing heterocyclic-lower alkyl groups such as phthalimidomethyl, succinimidomethyl and the like; cycloalkyl groups such as cyclohexyl and the like; lower alkoxy-lower alkyl groups such as methoxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl and the like; ar-lower alkoxy-lower alkyl groups such as benzyloxymethyl and the like; lower alkylthio-lower alkyl groups such as methylthiomethyl, 2-methylthioethyl and the like; arylthio-lower alkyl groups such as phenylthiomethyl and the like; lower alkenyl groups such as 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl and the like; substituted silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, tert-butylmethoxyphenylsilyl and the like.
The protecting groups for the hydroxyl group include all conventional groups usable as hydroxyl-protecting groups and there are mentioned, for example, acyl groups such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-(phenylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphonio)ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, S-benzylthiocarbonyl, 4-ethoxy-l-naphthyloxycarbonyl, 8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl, benzoyl and the like; lower alkyl groups such as methyl, tert-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl and the like; lower alkenyl groups such as allyl and the like; ar-lower alkyl groups such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, trityl and the like; oxygen-containing and sulfur-containing heterocyclic groups such as tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl and the like; lower alkoxy- and lower alkylthio-lower alkyl groups such as methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl and the like; lower alkyl- and aryl-sulfonyl groups such as methanesulfonyl, p-toluenesulfonyl and the like; substituted silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, tert-butylmethoxyphenylsilyl and the like; etc.
The substituent of the alkyl, alkenyl, cyclo-alkyl, aryl or heterocyclic group for R2; the substituent of the alkyl, alkenyl, cycloalkyl, aryl, alkoxy, alkylthio or amino group for R3; the substituent of the alkyl, alkenyl, cycloalkyl, aralkyl, aryl, alkoxy, alkylthio or amino group for R4; the substituent of the alkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group for R5; the substituent of the alkyl, alkoxy or alkylthio group for R6; the substituent of the alkyl, alkoxy or alkylthio group for R7; and the substituent of the alkyl for R7a include halogen atoms, cyano group, protected or unprotected carboxyl groups, protected or unprotected hydroxyl groups, protected or unprotected amino groups, protected or unprotected lower alkylamino groups, lower alkyl groups, lower alkoxy groups, lower alkoxycarbonyl groups, aryl groups, cycloalkyl groups, lower alkenyl groups and halogen atom-substituted lower alkyl groups, and the R2, R3, R4, R5, R6, R7 and R7a groups may be substituted by one or two or more of these groups.
Moreover, as the substituent of the alkyl for R7a, a halogen atom is preferable.
The ring comprising the boron atom which R8 and R9 form when taken together includes 5-membered to 8-membered rings containing at least one hetero atom selected from oxygen atom and nitrogen atom as the hetero atom forming the ring and condensed rings thereof, for example, 1,3,2-dioxaborolane, 1,3,2-dioxaborinane, 1,3,5,2-dioxazaborinane, 1,3,5,2-trioxaborinane, 1,3,6,2-trioxaborocane, 1,3,6,2-dioxazaborocane and the like.
The leaving group for X2 includes halogen atoms such as chlorine atom, bromine atom, iodine atom and the like; halogen-substituted or unsubstituted alkylsulfonyloxy groups such as methylsulfonyloxy, trifluoromethylsulfonyloxy and the like; and arylsulfonyloxy groups such as p-fluorophenylsulfonyloxy and the like.
As the alkyl group for R4a, a lower alkyl group is preferable.
Production Process IA 
Production Process IB 
wherein R1, R2, R3, R4, R5, R6, R8, R9, X1, X2, A and Z have the same meanings as mentioned above.
The compounds of the general formulas [1], [2], [2a], [3], [4], [5a] and [5b] may be in the form of salts. As the salts, there can be mentioned usually known salts at basic groups such as amino group and the like and at acidic groups such as hydroxyl group, carboxyl group and the like. As the salts at basic groups, there can be mentioned, for example, salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like; salts with organic carboxylic acids such as tartaric acid, formic acid, lactic acid, citric acid, trichloroacetic acid, trifluoroacetic acid and the like; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, naphthalenesulfonic acid and the like. Moreover, the salts at acidic groups, there can be mentioned, for example, salts with alkali metals such as sodium, potassium and the like; salts with alkaline earth metals such as calcium, magnesium and the like; salts with ammonium; salts with nitrogen-containing organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-b-phenethylamine, 1-ephenamine, N,Nxe2x80x2-dibenzyl-ethylenediamine and the like; etc.
Production Process IA
(1) Process for Producing Compound of the General Formula [1] or its Salt
The compound of the general formula [1] or its salt can be produced by subjecting a compound of the general formula [2] or its salt and a compound of the general formula [3] or its salt to coupling reaction using metallic palladium in the presence or absence of a base.
The solvent which is used in this reaction is not particularly limited as far as it does not adversely affect the reaction, and includes, for example, water; alcohols such as methanol, ethanol, propanol and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl Cellosolve and the like; esters such as ethyl acetate, butyl acetate and the like; ketones such as acetone, methyl ethyl ketone and the like; nitrites such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; sulfoxides such as dimethyl sulfoxide and the like; etc. These solvents may be used in admixture.
The base which is used, if desired, in this reaction includes, for example, potassium acetate, sodium hydrogencarbonate, sodium carbonate, potassium carbonate, triethylamine and the like. The amount of the base used is at least equal to the molar amount of, preferably 1 to 3 moles per mole of, the compound of the general formula [3] or its salt.
The metallic palladium used in this reaction includes, for example, palladium-activated carbon, palladium black and the like. The amount of the metallic palladium used is at least 0.00001 mole, preferably 0.001 to 0.05 mole, per mole of the compound of the general formula [3] or its salt.
The amount of the compound of the general formula [2] or its salt used is at least equal to the molar amount of, preferably 1.0 to 1.5 moles per mole of, the compound of the general formula [3] or its salt.
This coupling reaction may be usually carried out in an atmosphere of an inert gas (for example, argon, nitrogen) at 50-170xc2x0 C. for 1 minute to 24 hours.
Incidentally, the compound of the general formula [3] or its salt can be produced by, for example, the method described in WO97/29102.
Production Process IIA
(2.1) Process for Producing Compound of the General Formula [2a] or its Salt
The compound of the general formula [2a] or its salt can be produced by reacting a compound of the general formula [4] or its salt with a dialkoxyborane of the general formula [5a] or an alkoxydiborane of the general formula [5b] in the presence or absence of a base using a palladium catalyst selected from metallic palladium, palladium salts and palladium complexes.
The solvent which is used in this reaction may be any solvent as far as it does not adversely affect the reaction, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene and the like; aliphatic hydrocarbons such as n-hexane, cyclohexane and the like; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl Cellosolve and the like; esters such as ethyl acetate, butyl acetate and the like; ketones such as acetone, methyl ethyl ketone and the like; nitrites such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; sulfoxides such as dimethylsulfoxide and the like; etc. These solvents may be used in admixture.
The base which is used, if desired, in this reaction includes, for example, potassium acetate, potassium tert-butoxide, diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]-7-undecene, tributylamine, triethylamine and the like. The amount of the base used is at least equal to the molar amount of, preferably 1 to 3 moles per mole of, the compound of the general formula [4] or its salt.
The metallic palladium used in this reaction includes, for example, metallic palladium such as palladium-activated carbon, palladium black and the like; the palladium salt includes, for example, inorganic palladium salts such as palladium chloride and the like and organic palladium salts such as palladium acetate and the like; and the palladium complex includes, for example, organic palladium complexes such as tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) chloride, 1,1xe2x80x2-bis(diphenylphosphino)ferrocenepalladium(II) chloride and the like. The amount of a palladium catalyst selected from metallic palladium, palladium salt and palladium complex used may be at least 0.00001 mole, preferably 0.001 to 0.05 mole, per mole of the compound of the general formula [4] or its salt.
The dialkoxyborane which is used in this reaction includes, for example, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane, catecholborane and the like, and the alkoxydiborane includes, for example, 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-4xe2x80x2,4xe2x80x2,5xe2x80x2,5xe2x80x2-tetramethyl-140 ,3xe2x80x2,2xe2x80x2-dioxaborolane and the like.
The amount thereof used is at least equal to the molar amount of, preferably 1.0 to 1.5 moles per mole of, the compound of the general formula [4] or its salt.
This reaction may be carried out in an atmosphere of an inert gas (for example, argon, nitrogen) at 0-150xc2x0 C., preferably 80-110xc2x0 C., for 1-24 hours.
(2.2) Process for Producing Compound of the General Formula [1] or its Salt
The compound of the general formula [1] or its salt can be produced by adding the compound of the general formula [2a] or its salt produced in the above (2.1) without isolation to the reaction mixture and, if necessary, additionally adding a palladium catalyst, adding thereto the compound of the general formula [3] or its salt in the presence or absence of a base in an atmosphere of an inert gas (for example, argon, nitrogen), and further subjecting them to reaction.
When the compounds of the general formulas [2], [2a], [3] and [4] or their salts in the above-mentioned production process have isomers (for example, optical isomers, geometric isomers, tautomers and the like), these isomers can be used, and their solvates, hydrates and crystals of various forms can be used.
Furthermore, the amino groups of the compounds of the general formulas [2], [2a], [3] and [4] or their salts can be previously protected with a conventional protecting group and the protecting group can be removed in a manner known per se after the reaction.
The thus produced compound of the general formula [1] or its salt can be isolated and purified in at least one conventional manner such as extraction, crystallization, column chromatography or the like.
Among the compounds of the general formula [1] produced by the process of this invention, there can be mentioned, as preferable compounds, compounds of the general formula [1] wherein R2 is a substituted or unsubstituted cycloalkyl group; R3 is a hydrogen atom, a halogen atom or an alkyl group; R4is a hydrogen atom or an alkyl group; R5 is a hydrogen atom or an alkyl group; and A is CH or Cxe2x80x94R7 in which R7 is a halogen atom, a halogen-substituted or unsubstituted lower alkyl or lower alkoxy group. As representative compounds, there are mentioned, for example, the following compounds:
1-cyclopropyl-7-(isoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
8-chloro-1-cyclopropyl-7-(isoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
1-cyclopropyl-8-fluoro-7-(isoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
1-cyclopropyl-7-(isoindolin-5-yl)-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
1-cyclopropyl-7-(isoindolin-5-yl)-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
1-cyclopropyl-8-difluoromethoxy-7-(isoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
1-cyclopropyl-7-(isoindolin-5-yl)-8-trifluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
7-(7-chloroisoindolin-5-yl)-1-cyclopropyl-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
1-cyclopropyl-7-(7-fluoroisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
1-cyclopropyl-7-(7-fluoroisoindolin-5-yl)-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
1-cyclopropyl-7-(7-fluoroisoindolin-5-yl)-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
1-cyclopropyl-8-difluoromethoxy-7-(7-fluoroisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
1-cyclopropyl-7-(7-fluoroisoindolin-5-yl)-8-trifluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
1-cyclopropyl-8-methoxy-7-(7-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
1-cyclopropyl-7-(2-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
1-cyclopropyl-8-methyl-7-(2-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
1-cyclopropyl-8-methoxy-7-(2-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
1-cyclopropyl-8-difluoromethoxy-7-(2-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
1-cyclopropyl-7-(2-methylisoindolin-5-yl)-8-trifluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
(xc2x1)-1-cyclopropyl-7-(1-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
(xc2x1)-1-cyclopropyl-8-methyl-7-(1-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
(+)-1-cyclopropyl-8-methyl-7-(1-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
(xe2x88x92)-1-cyclopropyl-8-methyl-7-(1-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
(xc2x1)-1-cyclopropyl-8-methoxy-7-(1-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
(+)-1-cyclopropyl-8-methoxy-7-(1-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
(xe2x88x92)-1-cyclopropyl-8-methoxy-7-(1-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
(xc2x1)-1-cyclopropyl-8-difluoromethoxy-7-(1-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
(+)-1-cyclopropyl-8-difluoromethoxy-7-(1-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
(xe2x88x92)-1-cyclopropyl-8-difluoromethoxy-7-(1-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
1-cyclopropyl-7-(4-fluoroisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
1-cyclopropyl-7-(4-fluoroisoindolin-5-yl)-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
1-cyclopropyl-7-(4-fluoroisoindolin-5-yl)-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
1-cyclopropyl-8-difluoromethoxy-7-(4-fluoroisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
1-cyclopropyl-7-(4-fluoroisoindolin-5-yl)-8-trifluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
1-cyclopropyl-7-(6-fluoroisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
1-cyclopropyl-7-(6-fluoroisoindolin-5-yl)-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
1-cyclopropyl-7-(6-fluoroisoindolin-5-yl)-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
1-cyclopropyl-8-difluoromethoxy-7-(6-fluoroisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
1-cyclopropyl-7-(6-fluoroisoindolin-5-yl)-8-trifluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
1-cyclopropyl-7-(4,7-difluoroisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
1-cyclopropyl-7-(4,7-difluoroisoindolin-5-yl)-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
1-cyclopropyl-7-(4,7-difluoroisoindolin-5-yl)-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
1-cyclopropyl-7-(4,7-difluoroisoindolin-5-yl)-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, and
1-cyclopropyl-7-(4,7-difluoroisoindolin-5-yl)-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Furthermore, among the compounds of the general formula [2a] produced by the process of this invention, there can be mentioned, as preferable compounds, compounds of the general formula [2a] wherein R3 is a hydrogen atom, a halogen atom or an alkyl group; R4 is a hydrogen atom or an alkyl group; R5 is a hydrogen atom or an alkyl group; and Z is 1,1,2,2-tetramethylethylene, and as representative compounds, there are mentioned, for example, the following compounds:
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline,
7-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline,
7-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline,
7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline,
2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline,
1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline,
(xc2x1)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline,
(+)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline,
(xe2x88x92)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline,
4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline,
6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline, and
4,7-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline.

wherein R4a, R5, R8, R9 and X1 have the same meanings as mentioned above, R5a represents a substituted or unsubstituted alkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group, and R10 represents a hydrogen atom or a carboxyl-protecting group.
The compounds of the general formulas [2b], [4a], [6], [7], [8], [9] and [10] can also be used in the form of salts, and as the salts, there can be mentioned usually known salts at basic groups such as amino group and the like and at acidic groups such as hydroxyl group, carboxyl group and the like. The salt at basic group includes, for example, salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like; salts with organic carboxylic acids such as tartaric acid, formic acid, lactic acid, citric acid, trichloroacetic acid, trifluoroacetic acid and the like; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, naphthalenesulfonic acid and the like. Furthermore, the salt at acidic group includes, for example, salts with alkali metals such as sodium, potassium and the like; salts with alkaline earth metals such as calcium, magnesium and the like; salts with ammonium; salts with nitrogen-containing organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-b-phenethylamine, 1-ephenamine, N,Nxe2x80x2-dibenzylethylenediamine and the like; etc.
(1) Process for Producing Compound of the General Formula [9] or its Salt
The compound of the general formula [9] or its salt can be produced by reacting a compound of the general formula [10] or its salt with carbon dioxide, a halogenated formic acid ester or a carbonic acid ester in the presence of a base.
The solvent which is used in this reaction may be any solvent as far as it does not adversely affect the reaction, and includes, for example, aliphatic hydrocarbons such as n-hexane, cyclohexane and the like; ethers such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, dioxane and the like; etc. These solvents may be used in admixture.
The base which is used in this reaction includes, for example, alkyl metal or aryl metal reagents such as n-butyllithium, tert-butyllithium, phenyllithium, methyllithium and the like; and amide bases such as lithium diisopropylamide, lithium bistrimethylsilylamide and the like.
The halogenated formic acid ester includes, for example, methyl chloroformate, ethyl chloroformate and the like.
The carbonic acid ester includes, for example, dimethyl carbonate, diethyl carbonate, diphenyl carbonate and the like.
The amounts of the base and carbon dioxide, halogenated formic acid ester or carbonic acid ester used are at least 2 moles, preferably 2 to 3 moles, per mole of the compound of the general formula [10] or its salt.
This reaction may be usually carried out at xe2x88x9270 to 20xc2x0 C., preferably xe2x88x9250 to 0xc2x0 C., for 10 minutes to 24 hours.
The obtained compound of the general formula [9] or its salt may be used as it is without isolation in the subsequent reaction.
(2) Process for Producing Compound of the General Formula [8] or its Salt
The compound of the general formula [8] or its salt can be produced by subjecting the compound of the general formula [9] or its salt to halogenation reaction.
The solvent which is used in this reaction may be any solvent as far as it does not adversely affect the reaction, and includes, for example, carboxylic acids such as acetic acid and the like; halogenated hydrocarbons such as carbon tetrachloride and the like; inorganic acids such as sulfuric acid, hydrochloric acid and the like; water; etc. These solvents may be used in admixture.
The halogenating agent which is used in this reaction includes, for example, halogens such as chlorine, bromine, iodine and the like; organic halogen compounds such as N-bromosuccinimide, halogenated isocyanuric acids such as sodium N-bromoisocyanurate and the like; etc.
The amount of the halogenating agent used is at least equal to the molar amount of, preferably 1 to 1.5 moles per mole of, the compound of the general formula [9] or its salt.
This reaction may be carried out at xe2x88x9210 to 100xc2x0 C., preferably 0 to 30xc2x0 C., for 10 minutes to 24 hours.
The obtained compound of the general formula [8] or its salt may be used as it is without isolation in the subsequent reaction.
(3) Process for Producing Compound of the General Formula [4a] or its Salt
The compound of the general formula [4a] or its salt can be produced by reducing the compound of the general formula [8] or its salt to produce a compound of the general formula [6] or its salt and thereafter subjecting the compound of the general formula [6] or its salt to ring-closing reaction or alternatively by ring-closing the compound [8] or its salt to produce a compound of the general formula [7] or its salt and thereafter subjecting the compound of the general formula [7] or its salt to reduction reaction.
The solvent which is used in this reduction reaction may be any solvent as far as it does not adversely affect the reaction, and includes, for example, alcohols such as methanol, ethanol, isopropanol and the like; ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethylene glycol dimethyl ether and the like; nitrites such as acetonitrile and the like; amides such as N,N-dimethylformamide and the like; sulfoxides such as dimethylsulfoxide and the like; water; etc. These solvents may be used in admixture.
The reducing agent which is used in this reaction includes, for example, alkali metals such as lithium, sodium, potassium and the like; alkaline earth metals such as magnesium, calcium and the like; metals and their salts such as zinc, aluminum, chromium, titanium, iron, samarium, selenium, sodium hydrosulfite and the like; metal hydrides such as diisobutylaluminum hydride, trialkylaluminum hydride, tin hydride compound, hydrosilane and the like; borohydride complex compounds such as sodium borohydride, lithium borohydride, potassium borohydride, calcium borohydride and the like; aluminum hydride complex compounds such as lithium aluminum hydride and the like, etc.; boranes; alkylboranes; and the like.
The amount of the reducing agent used in this reaction is varied depending upon the kind of the reducing agent; however, at least 0.25 mole is required and, for example, in the case of the boron hydride complex compound, the above amount is at least 0.25 mole, preferably 0.25 to 2 moles, per mole of the compound of the general formula [8] or [7] or its salt.
This reaction may be carried out usually at xe2x88x9220 to 100xc2x0 C., preferably 0 to 50xc2x0 C., for 10 minutes to 24 hours.
The solvent which is used in this ring-closing reaction may be any solvent as far as it does not adversely affect the reaction, and includes, for example, ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethylene glycol dimethyl ether and the like; nitrites such as acetonitrile and the like, amides such as N,N-dimethylformamide and the like; sulfoxides such as dimethylsulfoxide and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; water; etc. These solvents may be used in admixture.
When the compound of the general formula [8] or its salt is subjected to ring-closing reaction to produce a compound of the general formula [7] or its salt, or when the compound of the general formula [6] or its salt is subjected to activation of its hydroxyl group and thereafter to ring-closing reaction to produce a compound of the general formula [4a] or its salt, the base which is if desired used includes, for example, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride and the like, and the amount of the base used is at least equal to the molar amount of, preferably 1 to 1.5 moles per mole of, the compound of the general formula [8] or [6] or its salt.
Furthermore, as the catalyst which is if desired used, a usually known phase transfer catalyst of quaternary ammonium salt is used; however, preferable are tetra-n-butylammonium bromide, tetra-n-butylammonium hydrogen-sulfate and the like. The amount of the catalyst used is 0.01 to 0.2 mole per mole of the compound of the formula [8] or [6] or its salt.
This reaction may be carried out at usually 0 to 100xc2x0 C., preferably 0 to 30xc2x0 C., for 10 minutes to 24 hours.
The obtained compound of the general formula [4a] or its salt may be used as it is without isolation in the subsequent reaction.
(4) Process for Producing Compound of the General Formula [2b] or its Salt
The compound of the general formula [2b] or its salt can be produced by subjecting the compound of the general formula [4a] or its salt to borodation.
Specifically, according to, for example, the method described in Jikken Kagaku Koza, 4th edition, Vol. 24, pages 61-90 (1992), it can be obtained by subjecting a compound of the formula [4b] or its salt to lithiation or Grignard reaction and thereafter to reaction with a trialkyl borate.
The solvent which is used in this reaction may be any solvent as far as it does not adversely affect the reaction, and includes, for example, aliphatic hydrocarbons such as n-hexane, cyclohexane and the like; ethers such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, dioxane and the like; etc. These solvents may be used in admixture.
The lithiating agent which is used in this reaction includes, for example, alkyl metal reagents such as n-butyllithium, tert-butyllithium, phenyllithium, methyllithium and the like; and amide bases such as lithium diisopropylamide, lithium bistrimethylsilylamide and the like. Moreover, the Grignard reagent can be obtained by reacting metallic magnesium with the compound represented by the general formula [4a] or its salt.
The trialkyl borate which is used in this reaction includes, for example, trimethyl borate, triethyl borate, triisopropyl borate, tributyl borate and the like.
The amount of the lithionizing agent, metallic magnesium or trialkyl borate used is at least equal to the molar amount of, preferably 1 to 2 moles per mole of, the compound of the general formula [4a] or its salt.
This reaction may be carried out usually at xe2x88x9270 to 50xc2x0 C., preferably xe2x88x9260 to 0xc2x0 C., for 10 minutes to 24 hours.
The obtained compound of the general formula [2b] or its salt may be used as it is without isolation in the subsequent reaction.
The thus obtained compound of the general formula [2b] or its salt can be subjected to, for example, protection or deprotection to be converted to the other compound of the general formula [2b] or its salt.
When the compounds of the general formula [2b], [4a], [6], [7], [8], [9] and [10] or their salts in the above-mentioned production process have isomers (for example, optical isomers, geometrical isomers, tautomers and the like), these isomers can be used, and their solvates, hydrates and crystals of various forms can also be used.
When the compounds of the general formulas [4a], [6], [7], [8], [9] and [10] or their salts have an amino group, a hydroxyl group or a carboxyl group, it is also possible to previously protect these groups with a conventional protecting group and remove the protecting group after the reaction in a manner known per se.
Next, the process for producing a compound of the general formula [1a] or its salt using the compound of the general formula [2b] or its salt as the starting material is explained.
Production Process IIB 
wherein R1, R2, R4a, R5, R6, R8, R9, X3 and A have the same meanings as mentioned above.
The compound of the general formula [1a] or its salt can be obtained by subjecting a compound of the general formula [3b] or its salt and the compound of the general formula [2b] or its salt to coupling reaction using a palladium complex catalyst in the presence or absence of a base.
The solvent which is used in this reaction may be any solvent as far as it does not adversely affect the reaction, and includes, for example, water; alcohols such as methanol, ethanol, propanol and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl Cellosolve and the like; esters such as ethyl acetate, butyl acetate and the like; ketones such as acetone, methyl ethyl ketone and the like; nitrites such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; sulfoxides such as dimethylsulfoxide and the like; etc. These solvents may be used in admixture.
The base which is used, if desired, in this reaction includes, for example, sodium hydrogencarbonate, sodium carbonate, potassium carbonate, triethylamine and the like.
The palladium complex catalyst which is used in this reaction includes, for example, inorganic palladium salts such as palladium chloride and the like; organic palladium salts such as palladium acetate and the like; and organic palladium complexes such as tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) chloride, 1,1xe2x80x2-bis(diphenylphosphino)ferrocenepalladium(II) chloride and the like.
The amount of the compound of the general formula [2b] or its salt used is at least equal to the molar amount of, preferably 1.0 to 1.5 moles per mole of, the compound of the general formula [3b] or its salt.
This coupling reaction may be carried out usually in an atmosphere of an inert gas (for example, argon, nitrogen) at 50 to 170xc2x0 C. for 1 minute to 24 hours.
The salt of the compound of the general formula [1a] includes, for example, the same salts as those mentioned as to the compounds of the general formulas [2b], [4a], [6], [7], [8], [9] and [10].
The compound of the general formula [3b] or its salt can be produced by, for example, the method described in WO97/29102.
Production Process IIIA 
wherein R4a, R5 and X1 have the same meanings as mentioned above; R5b, R5c and R5d may be the same or different and each represents an alkyl group; and Y represents a leaving group.
The leaving group for Y includes, for example, halogen atoms; lower alkylsulfonyloxy groups such as methylsulfonyloxy, ethylsulfonyloxy, isopropylsulfonyloxy and the like; arylsulfonyloxy groups such as phenylsulfonyloxy, naphthylsulfonyloxy and the like; etc.
Furthermore, as the alkyl groups for R5b, R5c and R5d, lower alkyl groups such as methyl group and the like are preferable.
The compounds of the general formulas [12] and [11] can also be converted to their salts, and as the salts, there can be mentioned usually known salts at basic groups such as amino group and the like. As the salts at the basic groups, there can be mentioned, for example, salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like; salts with organic carboxylic acids such as tartaric acid, formic acid, lactic acid, citric acid, trichloroacetic acid, trifluoroacetic acid and the like; salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, naphthalenesulfonic acid and the like; etc.
Furthermore, the salts of the compounds of the general formulas [6] and [4a] in the present production process include the same salts as mentioned as to Production Process IIA.
(1) Process for Producing Compound of the General Formula [6] or its Salt
The compound of the general formula [6] or its salt can be produced by reacting the compound of the general formula [12] or its salt with a formaldehyde or its derivative in the presence of an aryllithium.
The solvent which is used in this reaction may be any solvent as far as it does not adversely affect the reaction, and includes, for example, aliphatic hydrocarbons such as n-hexane, cyclohexane and the like; ethers such as diethyl ether, n-dibutyl ether, 1,2-dimethoxyethane, tetrahydrofuran, dioxane and the like. These solvents may be used in admixture.
The aryllithium which is used in this invention includes, for example, phenyllithium, biphenyllithium, naphthyllithium and the like.
The formaldehyde or its derivative includes, for example, formaldehyde, paraformaldehyde, trioxane and the like.
The amounts of the aryllithium and the formaldehyde or its derivative used are at least 2 moles, preferably 2 to 5 moles, per mole of the compound of the general formula [12] or its salt.
This reaction may be carried out at usually xe2x88x9270 to 50xc2x0 C., preferably xe2x88x9230 to 30xc2x0 C., for 10 minutes to 24 hours.
The obtained compound of the general formula [6] or its salt may be used as it is without isolation in the subsequent reaction.
Moreover, the amino-protecting group may be subjected to elimination reaction after the reaction and a new amino-protecting group may be introduced.
(2) Process for Producing Compound of the General Formula [11] or its Salt
The compound of the general formula [11] or its salt can be produced by reacting the compound of the general formula [6] or its salt with a halogenating agent, a sulfonylating agent or the like in the presence or absence of a base.
The solvent which is used in this reaction may be any solvent as far as it does not adversely affect the reaction, and includes, for example, aliphatic hydrocarbons such as n-hexane, cyclohexane and the like; halogenated hydrocarbons such as methylene chloride, chloroform and the like; ethers such as tetrahydrofuran, 1,2-dimethoxyethane, dioxane and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; sulfoxides such as dimethylsulfoxide and the like; amides such as N,N-dimethylformamide and the like; esters such as ethyl acetate and the like; nitrites such as acetonitrile and the like; etc. These solvents may be used in admixture.
Moreover, the base which is used, if necessary, includes, for example, organic and inorganic bases such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU), pyridine, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium hydride and the like.
The halogenating agent includes, for example, phosphorus oxychloride, phosphorous oxybromide, phosphorus trichloride, phosphorus pentachloride, thionyl chloride and the like.
The sulfonylating agent includes, for example, methanesulfonyl chloride, p-toluenesulfonyl chloride and the like.
The amount of the halogenating agent or sulfonylating agent used and the amount of the base which is used, if necessary, are at least equal to the molar amount of, preferably 1 to 5 moles per mole of, the compound of the general formula [6] or its salt.
This reaction may be carried out at usually xe2x88x9210 to 100xc2x0 C., preferably 0 to 50xc2x0 C., for 10 minutes to 24 hours.
The salt of the obtained compound of the general formula [11] or its salt may be used as it is without isolation in the subsequent reaction.
(3) Process for Producing Compound of the General Formula [4a] or its Salt
The compound of the general formula [4a] or its salt can be produced by subjecting the compound of the general formula [11] or its salt to ring-closing reaction in the presence of a base and in the presence or absence of a catalyst.
The solvent which is used in this reaction may be any solvent as far as it does not adversely affect the reaction, and includes, for example, aliphatic hydrocarbons such as n-hexane, cyclohexane and the like; aromatic hydrocarbons such as benzene, toluene and the like; ethers such as tetrahydrofuran, dioxane, diethylene glycol dimethyl ether, di-n-butyl ether and the like; halogenated hydrocarbons such as methylene chloride, chloroform and the like; nitrites such as acetonitrile and the like; amides such as N,N-dimethylformamide and the like; sulfoxides such as dimethylsulfoxide and the like; water; etc. These solvents may be used in admixture.
The base which is used in this reaction includes, for example, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium hydride and the like.
As the catalyst which is used, if necessary, there are used phase transfer catalysts of usually known quaternary ammonium salts. However, preferably, there are mentioned tetra-n-butylammonium bromide, tetra-n-butylammonium hydrogensulfate and the like.
The amount of the base used is at least equal to the molar amount of, preferably 1 to 10 moles per mole of, the compound of the general formula [11] or its salt, and the amount of the catalyst which is used, if necessary, is 0.01 to 0.2 mole per mole of the compound of the general formula [11] or its salt.
This reaction may be carried out at usually 0 to 100xc2x0 C., preferably 0 to 40xc2x0 C., for 10 minutes to 24 hours.
The compound of the general formula [4a] or its salt may be used as it is without isolation in the subsequent reaction.
Furthermore, if necessary, after the removal of the protecting group of R5, a new protecting group may be introduced into the compound of the general formula [4a] or its salt taking the subsequent production route into consideration.
When the compounds of the general formulas [4a], [6], [11] and [12] or their salts in the above-mentioned production process have isomers (for example, optical isomers, geometrical isomers, tautomers and the like), these isomers can be used. Also, solvates, hydrates and crystals of various forms can be used.
Moreover, when the compounds of the general formulas [4a], [6], [11] and [12] or their salts have an amino group, a hydroxyl group or a carboxyl group, it is possible to previously protect these groups with a conventional protecting group and remove the protecting group after the reaction in a manner known per se.
Next, a process for producing a compound of the general formula [1a] or its salt using the compound of the general formula [4a] or its salt as the starting material is explained.
Production Process IIIB 
wherein R1, R2, R4a, R5, R6, R8, R9, A, X1 and X have the same meanings as mentioned above.
(1) Process for Pproducing Compound of the General Formula [2b] or its Salt
The compound of the general formula [2b] or its salt can be produced by subjecting the compound of the general formula [4a] or its salt to borodation.
Specifically, it can be obtained by subjecting the compound of the general formula [4a] or its salt to lithiation or Grignard reaction according to, for example, the method described in Jikken Kagaku Koza, 4th edition, Vol. 24, pages 61-90 (1992), and thereafter to reaction with trialkyl borate.
The solvent which is used in this reaction may be any solvent as far as it does not adversely affect the reaction, and includes, for example, aliphatic hydrocarbons such as n-hexane, cyclohexane and the like; ethers such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, dioxane and the like; etc. These solvents may be used in admixture.
The lithiating agent which is used in this reaction includes, for example, alkyl metal or aryl metal reagents such as n-butyllithium, tert-butyllithium, phenyllithium, methyllithium and the like; and amide bases such as lithium diisopropylamide, lithium bistrimethyl-silylamide and the like. Moreover, the Grignard reagent can be obtained by reacting metallic magnesium with the compound represented by the formula [4a] or its salt.
The trialkyl borate which is used in this reaction includes, for example, trimethyl borate, triethyl borate, triisopropyl borate, tributyl borate and the like.
The amounts of the lithiating agent, metallic magnesium and trialkyl borate used are at least equal to the molar amount of, preferably 1 to 2 moles per mole of, the compound of the general formula [4a] or its salt.
This reaction may be carried out at usually xe2x88x9270 to 50xc2x0 C., preferably xe2x88x9260 to 0xc2x0 C., for 10 minutes to 24 hours.
The obtained compound of the general formula [2b] or its salt may be used as it is without isolation in the subsequent reaction.
(2) Process for Producing Compound of the General Formula [la] or its Salt
The compound of the general formula [1a] or its salt can be obtained by subjecting the compound of the general formula [2b] or its salt and the compound of the general formula [3] or its salt to coupling reaction using a palladium catalyst in the presence or absence of a base.
The solvent which is used in this reaction is not particularly limited as far as it does not adversely affect the reaction, and includes, for example, water; alcohols such as methanol, ethanol, propanol and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, ethylene glycol dimethyl ether and the like; esters such as ethyl acetate, butyl acetate and the like; ketones such as acetone, methyl ethyl ketone and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; sulfoxides such as dimethylsulfoxide and the like; etc. These solvents may be used in admixture.
The base which is used, if desired, in this reaction includes, for example, sodium hydrogencarbonate, sodium carbonate, potassium carbonate, triethylamine and the like, and the amount of the base used is at least equal to the molar amount of, preferably 2 to 5 moles per mole of, the compound of the general formula [3] or its salt.
Moreover, the palladium catalyst which is used in this reaction includes, for example, metallic palladium such as palladium-activated carbon, palladium black and the like; inorganic palladium salts such as palladium chloride and the like; organic palladium salts such as palladium acetate and the like; and organic palladium complexes such as tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) chloride, 1,1xe2x80x2-bis(diphenylphosphino)ferrocenepalladium(II) chloride and the like.
The amount of the palladium catalyst used is at least 0.00001 mole, preferably 0.001 to 0.05 mole, per mole of the compound of the general formula [3] or its salt.
The amount of the compound of the general formula [2b] or its salt used is at least equal to the molar amount of, preferably 1.0 to 1.5 moles per mole of, the compound of the general formula [3] or its salt.
This coupling reaction may be carried out usually in an atmosphere of an inert gas (for example, argon, nitrogen) at 50 to 170xc2x0 C. for 1 minute to 24 hours.
The salts of the compounds of the general formulas [1a], [2b] and [3] in Production Process IIIB include the same salts as explained above.
The compound of the general formula [3] or its salt can be produced by, for example, the method described in WO97/29102.
Production Process IVA 
wherein R1b, R2a and R7a have the same meanings as mentioned above; R1a represents a carboxyl-protecting group; and X represents a halogen atom.
As the compounds of the general formulas [3a] and [13] to [19] can be converted to their salts, and as these salts, there can be mentioned usually known salts at basic groups such as amino group and the like and at acidic groups such as hydroxyl group, carboxyl group and the like. The salts at the basic groups include, for example, salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like; salts with organic carboxylic acids such as tartaric acid, formic acid, lactic acid, citric acid, trichloroacetic acid, trifluoroacetic acid and the like; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, naphthalenesulfonic acid and the like. Also, the salts at the acidic groups include, for example, salts with alkali metals such as sodium, potassium and the like; salts with alkaline earth metals such as calcium, magnesium and the like; salts with ammonium; salts with nitrogen-containing organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-b-phenethylamine, 1-ephenamine, N,Nxe2x80x2-dibenzylethylenediamine and the like; etc.
(1) Process for Producing Compound of the Ceneral Formula [15] or its Salt
The compound of the general formula [15] or its salt can be produced by reacting a compound of the general formula [13] or its salt with a compound of the general formula [14] in the presence or absence of a base.
The solvent which is used in this reaction may be any solvent as far as it does not adversely affect the reaction, and includes, for example, aliphatic hydrocarbons such as n-hexane, cyclohexane and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, dioxane and the like; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; nitrites such as acetonitrile and the like; sulfoxides such as dimethylsulfoxide and the like; water; etc. These solvents may be used in admixture. Moreover, when water is used as the solvent, the use of a usually known phase transfer catalyst is effective.
The phase transfer catalyst used includes, for example, quaternary ammonium salts such as tetramethylammonium bromide, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogensulfate and the like. When the phase transfer catalyst is used, the amount thereof used is at least 0.1 mole, preferably 0.3 to 1.0 mole, per mole of the compound of the general formula [13] or its salt.
As the base which is used, if desired, there are mentioned sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, potassium carbonate, potassium tert-butoxide, sodium hydride and the like.
The amounts of the base and the compound of the general formula [14] used is each at least equal to the molar amount of, preferably 1 to 10 moles per mole of, the compound of the general formula [13] or its salt.
This reaction may be carried out usually at 0 to 180xc2x0 C. for 5 minutes to 30 hours.
The obtained compound of the general formula [15] or its salt may be used as it is without isolation in the subsequent reaction.
(2) Process for Producing Compound of the General Formula [16] or its Salt
The compound of the general formula [16] or its salt can be obtained by subjecting the compound of the general formula [15] or its salt to conventional elimination reaction of carboxyl-protecting group.
(3) Process for Producing Compound of the General Formula [17] or its Salt
The compound of the general formula [17] or its salt can be obtained by subjecting the compound of the general formula [16] or its salt to ketoesterification reaction usually known in this field.
(3-a) The compound of the general formula [17] or its salt can be obtained by activating the carboxyl group of the compound of the general formula [16] or its salt according to the method described in Angew. Chem. Int. Ed. Engl., Vol. 18, page 72 (1979), for example, by converting the carboxyl group to an active acid amide form or the like using N,Nxe2x80x2-carbonyldiimidazole, and thereafter reacting the activated species with a magnesium salt of a malonic acid monoester.
The solvent which is used in this reaction is not particularly limited as far as it does not adversely affect the reaction, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, diethyl ether and the like; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like; and amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like. These solvents may be used in admixture.
The amount of the magnesium salt of a malonic acid monoester used is at least equal to the molar amount of, preferably 1 to 2 moles per mole of, the compound of the general formula [16] or its salt.
This reaction may be carried out at usually 0 to 100xc2x0 C., preferably 10 to 80xc2x0 C., for 5 minutes to 30 hours.
(3-b) Alternatively, the compound of the general formula [17] or its salt can be obtained by, for example, converting the carboxyl group of the compound of the general formula [16] or its salt to an acid halide using a halogenating agent such as thionyl chloride or the like, thereafter reacting the acid halide with a salt of a malonic acid diester with a metal such as sodium, ethoxy-magnesium or the like, and then subjecting the reaction product to partial removal of the carboxyl-protecting group and decarbonization reaction using p-toluenesulfonic acid or trifluoroacetic acid in a water-containing solvent.
The solvent which is used in the reaction of the acid halide with the metal salt of a malonic acid diester is not particularly limited as far as it does not adversely affect the reaction, and specifically includes the same solvents as in (3-a) above.
The amount of the metal salt of a malonic acid diester used is at least equal to the molar amount of, preferably 1 to 3 moles per mole of, the compound of the general formula [16] or its salt.
This reaction may be carried out usually at xe2x88x9250 to 100xc2x0 C. for 5 minutes to 30 hours.
(4) Process for Producing Compound of the General Formula [19] or its Salt
(4-a) The compound of the general formula [19] or its salt can be obtained by reacting the compound of the general formula [17] or its salt with an orthoester such as methyl orthoformate, ethyl orthoformate or the like in acetic anhydride and thereafter reacting the reaction product with a compound of the general formula [18] or its salt.
The solvent which is used in this reaction is not particularly limited as far as it does not adversely affect the reaction, and include, for example, aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, methyl Cellosolve and the like; alcohols such as methanol, ethanol, propanol and the like; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; sulfoxides such as dimethyl sulfoxide and the like; etc. These solvents may be used in admixture.
The amount of the orthoester used is at least equal to the molar amount of, preferably 1 to 10 moles per mole of, the compound of the general formula [17] or its salt. These reactions may be carried out at usually 0 to 150xc2x0 C., preferably 50 to 150xc2x0 C., for 20 minutes to 50 hours.
In order to subsequently react the compound of the general formula [18] or its salt, it is sufficient to use this compound of the general formula [18] or its salt in an amount at least equal to the molar amount of the compound of the general formula [17] or its salt and it is sufficient to carry out the reaction at usually 0 to 100xc2x0 C., preferably 10 to 60xc2x0 C., for 20 minutes to 30 hours.
(4-b) Alternatively, the compound of the general formula [19] or its salt can also be derived by reacting the compound of the general formula [17] or its salt with an acetal such as N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide diethylacetal or the like in the presence or absence of an acid anhydride such as acetic anhydride or the like and thereafter reacting the reaction product with the compound of the general formula [18] or its salt.
When the acid anhydride is used, the amount thereof used is at least equal to the molar amount of, preferably 1 to 5 moles per mole of, the compound of the general formula [17] or its salt.
The solvent which is used in this reaction is not particularly limited as far as it does not adversely affect the reaction, and specifically includes the same solvents as in (4-a) above.
The amount of the acetal used is at least equal to the molar amount of, preferably about 1 to 5 moles per mole of, the compound of the general formula [17] or its salt.
These reactions may be carried out at usually 0 to 100xc2x0 C., preferably 20 to 85xc2x0 C., for 20 minutes to 50 hours.
In order to subsequently react the compound of the general formula [18] or its salt, it is sufficient to use this compound of the general formula [18] or its salt in an amount at least equal to the molar amount of the compound of the general formula [17] or its salt and it is sufficient to carry out the reaction at usually 0 to 100xc2x0 C., preferably 10 to 60xc2x0 C. for 20 minutes to 30 hours.
(5) Process for Producing Compound of the General Formula [3a] or its Salt
The compound of the general formula [3a] or its salt can be obtained by subjecting a compound of the general formula [19] or its salt to ring-closing reaction in the presence or absence of a fluoride salt or a base.
The solvent which is used in this reaction is not particularly limited as far as it does not adversely affect the reaction, and includes, for example, amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; ethers such as dioxane, anisole, diethylene glycol dimethyl ether, dimethyl Cellosolve and the like; sulfoxides such as dimethyl sulfoxide and the like; water; etc. These solvents may be used in admixture.
The fluoride salt which is used, if desired, in this reaction includes, for example, sodium fluoride, potassium fluoride and the like.
The base which is used, if desired, in this reaction includes, for example, sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, potassium carbonate, potassium tert-butoxide, sodium hydride and the like.
The amounts of the fluoride salt and base used is each at least equal to the molar amount of, preferably 1.0 to 3.0 moles per mole of, the compound of the general formula [19] or its salt. This reaction may be carried out usually at 0 to 180xc2x0 C. for 5 minutes to 30 hours.
The obtained compound of the general formula [3a] or its salt may be used as it is without isolation in the subsequent reaction.
The thus obtained compound of the general formula [3a] or its salt can be converted to the other compounds of the general formula [3a] or their salts by subjecting the former to protection reaction and/or deprotection reaction.
When the salts of the compounds of the general formulas [3a] and [13] to [19] or their salts in the above-mentioned production process have isomers (for example, optical isomers, geometrical isomers, tautomers and the like), these isomers can be used, and solvates, hydrates and crystals of various forms can also be used.
Furthermore, when the compounds of the general formulas [3a] and [13] to [19] or their salts have an amino group, a hydroxyl group or a carboxyl group, it is possible to previously protect these groups with a conventional protecting group and remove the protecting group after the reaction in a manner known per se.
Next, a process for producing a compound of the general formula [lb] or its salt using the compound of the general formula [3a] or its salt as the starting material is explained. 
wherein R1, R1b, R2a, R3, R4, R5, R7a, R8 and R9 have the same meanings as mentioned above.
The compound of the general formula [1b] or its salt can be produced by subjecting the compound of the general formula [2] or its salt and the compound of the general formula [3a] or its salt to coupling reaction using a palladium catalyst in the presence or absence of a base.
The solvent which is used in this reaction is not particularly limited as far as it does not adversely affect the reaction, and includes, for example, water; alcohols such as methanol, ethanol, propanol and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl Cellosolve and the like; esters such as ethyl acetate, butyl acetate and the like; ketones such as acetone,.methyl ethyl ketone and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; sulfoxides such as dimethyl sulfoxide and the like; etc. These solvents may be used in admixture.
The base which is used, if desired, in this reaction includes, for example, sodium hydrogencarbonate, sodium carbonate, potassium carbonate, triethylamine and the like.
The palladium catalyst which is used in this reaction includes, for example, metallic palladiums such as palladium-activated carbon, palladium black and the like; inorganic palladium salts such as palladium chloride and the like; organic palladium salts such as palladium acetate and the like; and organic palladium complexes such as tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) chloride, 1,1xe2x80x2-bis(diphenylphosphino)ferrocenepalladium(II) chloride and the like.
The amount of the palladium catalyst used is at least 0.01% by mole, preferably 0.1 to 1.0% by mole, based on the amount of the compound of the general formula [3a] or its salt.
The amount of the compound of the general formula [2] or its salt used is at least equal to the molar amount of, preferably 1.0 to 1.5 moles per mole of, the compound of the general formula [3a] or its salt.
This coupling reaction may be carried out usually in an atmosphere of an inert gas (for example, argon, nitrogen) at 50 to 170xc2x0 C. for 1 minute to 24 hours.
The salts of the compound of the general formula [1b] include the same salts as the above-mentioned salts of the compounds of the general formulas [3a] and [13] to [19].
The compound of the general formula [2] or its salt can be produced by, for example, the method described in WO97/29102 and the above Production Processes IB and IIA.
The salts of the compound of the general formula [2] include the same salts as the above-mentioned salts of the compounds of the general formulas [3a] and [13] to [19].
In order to produce (R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (T-3811) methanesulfonate, it is sufficient to produce the same by a usually known process for producing a salt of a compound. Specifically, T-3811 methanesulfonate can be obtained by suspending or dissolving T-3811 in, for example, an alcohol such as methanol, ethanol or the like; N,N-dimethylformamide; a methanol-ether mixed solvent; or the like, adding methanesulfonic acid to the resulting suspension or solution to react with T-3811.
Moreover, T-3811 methanesulfonate can also be produced by dehydrating T-3811 methanesulfonate monohydrate in a solvent, for example, an alcohol such as methanol, ethanol or the like; N,N-dimethylformamide; a methanolether mixed solvent; or the like.
In order to produce T-3811 methanesulfonate monohydrate, it is sufficient to produce the same by a usually known method for producing a hydrate of salt of a compound. Specifically, T-3811 methanesulfonate monohydrate can be produced by, for example, suspending or dissolving T-3811 in a water-containing alcohol such as water-containing ethanol, water-containing isopropanol or the like; water-containing acetonitrile; water-containing acetone; water-containing tetrahydrofuran; water-containing acetic acid; water-containing N,N-dimethylformamide; water; or the like, adding methanesulfonic acid to the resulting suspension or solution to react with T-3811.
When T-3811 methanesulfonate or its monohydrate is used as an active ingredient to prepare a composition thereof with an inactive ingredient, it is preferable to prepare a preparation composition in which the inactive ingredient is a carrier acceptable as preparation.
The carrier acceptable as preparation which is used in this invention includes specifically excipients such as lactose, corn starch, crystalline cellulose, mannitol, erythritol, sucrose and the like; disintegrators such as sodium carboxymethyl starch, calcium carmellose, sodium croscarmellose, hydroxypropyl cellulose of a low substitution degree, crospovidone and the like; binders such as hydroxypropyl cellulose, povidone, methyl cellulose and the like; lubricants such as magnesium stearate, calcium stearate, talc, light anhydrous silicic acid and the like; coating agents such as hydroxypropylmethyl cellulose, ethyl cellulose, polyvinyl alcohol, methacrylic acid copolymer, hydroxypropylmethyl cellulose acetate succinate and the like; plasticizers such as macrogol, glycerine triacetate, triethyl citrate and the like; coloring agents such as iron sesquioxide, yellow iron sesquioxide, food yellow No. 5, titanium oxide and the like; sweetening agents such as sodium saccharate, aspartame, hydrogenated maltose starch and the like; viscosity improvers such as gelatine, sodium alginate and the like; tonicity agents such as mannitol, glucose, xylitol and the like; pH-adjusting agents such as methanesulfonic acid, sodium lactate solution and the like; solvents such as water for injection and the like; surface active agents such as polysorbate 80, sorbitan aliphatic acid ester, macrogol 400 and the like; ointment bases such as white vaseline, polyethylene glycol, propylene glycol, cetanol and the like; etc.
Furthermore, the amount of the T-3811 methanesulfonate or its monohydrate contained in the composition is usually 0.05 to 70% by weight, preferably 0.5 to 20% by weight, based on the weight of the composition.
The composition of this invention can be prepared in various dosage forms, for example, internal solid and liquid dosage forms such as tablet, capsule, granule, pilule, grain, powder, syrup and the like; solutions such as injection, eye drop and the like; hemi-solid dosage forms such as ointment, cream, gel, jelly and the like.
The dosage regimen, dose and number of administrations of the composition of this invention can be appropriately selected depending upon the symptom of patient, and it is usually sufficient to administer the composition in a proportion of 0.1 to 100 mg/kg per day per adult in terms of T-3811 in one to several portions.
Next, the solubility of various salts of T-3811 is explained.
The solubility of each salt of T-3811 was determined by the following method:
To about 50 mg of each salt of T-3811 is added 2 ml of distilled water and they are stirred and mixed. This sample solution is exposed to ultrasonic wave irradiation (SOLID STATE 1,200, Cho-onpa Kogyo) in cold water for 3 hours and then filtered through a filter with a pore size of 0.45-xcexcm (MILLEX-HV13, MILLIPORE). The T-3811 content in this filtrate is determined by a liquid chromatography.
The results obtained are shown in Table 1.