CA1341009C - Intermediates for preparing 4-oxyquinoline-3-carboxylic acid derivatives - Google Patents

Abstract

Compounds of the formula wherein R1 is a fluorinated methoxy group, R3a is a hydrogen atom, a nitro group or an amino group, and X
is a halogen atom are intermediates for preparing compounds of the formula (I):

Description

This appl.icati.on is a division of Canadian Patent Application 606,15'7, filed July 19, 1989 (now Canadian Patent l, 335, 670) .
The present invention relates to a series of novel 8-(fluorinated methoxy)-4-oxoquinoline-carboxylic acid derivatives which have been found to have valuable and powerful antibacterial activity. The invention also provides compositions containing these compounds, intermediates useful in their preparation, and processes for preparing them.
The compounds of the present invention are 1-cyclopropyl-4-oxo-6-flu.oro-7-(optionally substituted heterocyclic)-8-(fluorinated methoxy)-quinoline-3-carboxylic acid derivatives and 1-cyclopropyl-4-oxo-5-amino-6-fluoro-7-(optiona.l.ly substituted heterocyclic)-8-(fluorinated methoxy)-quinoline-3-carboxylic acid derivatives.
It is an unfortunate fact of modern medicine that many infectious bacaeria are gradually developing resistance to the antibic>tics commonly used to treat infection caused by them, with the result that known antibacterial agents are increasingly becoming of limited effectiveness. There is, therefore, a continuing need to develop new antibacterial agents, which may, even if only for a restricted period, be effective against infectious bacteria. Most of the common antibacterial agent=s in present day use were originally developE:d from fermentation products, although some are of wholly synthetic origin.
There have been proposals to use certain 4-oxoquinoline-3-c<~rboxy~_ic acid derivatives as ~'7 antibacterial agents. For example, European Patent Publication No. 78 362, May 11, 1983 discloses a limited class of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)quinol:ine-3-carboxylic acid derivatives, in which the piperazinyl group is unsubstituted or has a methyl, ethyl or p-hydroxyethyl :aubstituent at the 4-position. These compounds resemble certain of those of the present invention, except that they 1<~ck the 8-fluorinated methoxy group which has been found to be critical to the achievement of the excellent activity of the compounds of the present invention.
European Patent Publications No. 106 489, April 24, 1985, No. 153 163, August 28, 1985, No. 230 295, July 27, 1987, No. 235 762, September 9. 1987, and No. 241 206, October 14, 1987, disclose classes of quinoline derivatives, including amongst many others, some 1-substituted-4-oxo-1,4-dihydro-6-halo-7-(optionally substituted heterocyclic)-8-substituted-quinoline-3-carboxylic acid derivatives, of which in some the 8-subst;ituent is an alkoxy group, but do not disclose any compounds in which the 8-substituent is a fluorinated methoxy group.
Of the compounds di:aclosed in European Patent Publication No. 78 362, one, namely Norflexacin, whose systematic name is 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinol_ine-3~-carboxylic acid, is disclosed in The Merck Index Tenth Edition, published in 1983, monograph number 6541. In common with the other compounds of European Patent Publication No. 713 362, this lacks the critical 8-~3t,~ ~~9 fluorinated methoxy substituent of the present invention.
We have surprisingly found that the combination of a limited class of 8-fluorinated methoxy substituents with certain limited and highly specific classes of heterocyclic substituent at the 7-position and optionally an amino group at the 5-position leads to the production of compounds which have unexpectedly good antibacterial activities against Gram positive and Gram negative bacteria, in many cases far surpassing those of the prior art compounds. In particular, the compounds of the present invention have surprisingly good activity against several Gram positive bacteria against which the known compounds are ineffective or are effective only at high concentrations, for example Staphylococcus aureus and Enterococcus faecalis.
It is believed that the closest prior art is the aforementioned European Fatent Publications No. 78 362, No.
230 295 and No. 241 206. We have surprisingly found that compounds of the present invention show an exceptional antibacterial activity against penicillin- and cephalosporin-resistant Gram positive bacteria and Pseudomonas aeruginosa, which can be controlled only with difficulty with t3-lactam antibiotics, and wr,ich are therefore, a major problem in medicine.
The present invention provides a series of 1,4-dihydro-4-oxoquinoline-3-carboxylic acid derivatives which have exceptional antibaca erial. activity. The invention also provides processes for preparing them, intermediates useful in their preparation, and pharmaceutical compositions containing such a duinoline derivative as an antibacterial agent.
a j 134 pp9 The compounds of the present invention are those compounds of formula (I):

F C C COOH
\ // \ / \ /
C' C C
II II
C' C CH (I) / \\ / \ /

I
Rl CH
/ \

in which R1 represent;a a methoxy group having at least one fluorine sub;~tituent;
R2 represent:~ a group selected from the group consisting ol.:
(i) groups of formula (II):
.-_.
I I (ti) ):;4-N N-\ J( A (R5)m in which:
R4 represents a hydrogen atom; a hydroxy group; an amino group; a C1 - C6 alkyl group; a substituted C1 - C6 alkyl group having at least one substituent; selected from the group consisting of substituentf~ (a), defined below; an aralkyl 1341 ppg group; ~~ Cl - C6 aliphatic acyl group; or a substituted C,z - C6 aliphatic acyl group having at least one ;substituent selected from the group consisting of substituents (a), defined below;
R5 represents a hydrogen atom, a C1 - C6 alkyl group or. a substituted C1 - C6 alkyl group having at least one substituent selected from the group consisting of substituents (b), defined below;
A represents an ethylene group, a trimethylene group, o~r a gi:oup of formula -COCH2-, and m represents 1. or 2;
(ii) groups of formula (III):
(CH2)n I I (III) R~-~ N-\ X

in which:
R6 represents a hydrogen atom; a C1 - C6 alkyl group; a substituted C1 - C6 alkyl group having at least one substituent selected from the group consisting of substituents (b), defined below; a hydroxy <~roup; a C1 - C6 alkoxy group; or a C1 - C6 <~lkoxy group having at least one fluorine substituent;
R~ represents a group of formula R8R9N-(CH2)q-, in which R8 and R9 are independently selected from the group consisting of hydrogen atoms, C1 - C6 alkyl groups and aralkyl groups, and g represents 0 or 1; a hydroxy group; or a C - C

alkoxy group;
B represents a~ methylene group, an ethylene group, a trimethylene grroup, or a tetramethylene group; and n represents 1. or 2;
(iii) groups of formula (IV):

// X
o .
I ~) ( IV) -N
in which:
R10 represents a hydrogen atom or a Cl - C6 alkyl group;
and (iv) groups of foi:mula (V):
._.
/ \ , Z N-~ (V) \ /
in which:
Z represents a oxygen atom or a sulfur atom;
R3 represents a hydrogen atom or an aminoigroup;

1 34~ pp9 substituents (a):.
hydroxy groups, Cl - C6 alkoxy groups, C2 - C6 aliphatic acyloxy groups, C1 - C6 aliphatic acyl groups, car;boxy groups, C2 - C6 alkoxycarbonyl groups, sul:Eo groups, amino groups, C - C

aliphatic acylamino groups, and mono- and di-(C1 - C6 alkyl) substituted amino groups;
substituents (b) hydroxy groups, C.~ - C6 alkoxy groups, and halogen atoms; and said aralkyl.,groups have from 1 to 4 carbon atoms in the alkyl part amd have an aryl part Which has from 6 to 10 carbon atoms. and which is unsubstituted or has at least one substitu:ent selected from the group consisting of substituents (c), defined below;
substituents (c):
hydroxy groups, Cl. - C6 alkyl groups. C1 - C6 alkoxy groups, C2 - C6 aliphatic acyloxy groups, C1 - C6 aliphatic acyl groups, carboxy groups, C2 - C6 alkoxycarb~onyl groups, sulfo groups, nitro groups, cyano groups, amino groups, C - C

aliphatic acylamin.o groups, and mono- and di-(Cl - C6 alkyl) substituted amino groups;
and pharmaceutically acceptable salts, esters and amides thereof .
The invention also provides a pharmaceutical composition :Eor the treatment of bacterial infections, comprising a~1 effective amount of an antibacterial agent in combination with a pharmaceutically acceptable carrier or diluent, wherein the antibacterial agent is selected from the group consisting of compounds of formula (I) and pharmaceutically-acceptable salts, esters and amides thereof.
The invention also provides methods of preparing the compounds of the invention, which are described in more detail hereafter.
The invention also provides the following intermediates for preparing the compounds of formula (I):
30.
cooH ~ i ( ( COON
w $F~
R O"
F ~~0. ~ coo sz'o ~ 30. ~ ~; o F ~ i I
~N' L~ ~ R 1 wherein R1 is a fluorinated methoxy group, R3a is hydrogen atom, a nitro group or an amino group, RlOa is a lower alkyl group, and X is a halogen atom.
In the compoun~~s of t;he present invention, R1 represents a methoxy group having at least one fluorine substituent, which may be a monofluoromethoxy group, a difluoromethoxy group or a trifluoromethoxy group, of which the difluoromethoxy and trifluoromethoxy groups are preferred.
Where R- :repre:>ents a group of formula ( I I ) and R9 represents an alkyl group, this may be a straight or branched chain alkyl group containing from 1 to 6, preferably 1 to 4, carbon atoms, and a}samples of such groups include the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, t-pentyl, hexyl and 1,3-dimethylbutyl groups. Of these, the methyl, ethyl, prop5~l, isopropyl, butyl and isobutyl groups are preferred. Such al~;yl groups may be m1 ....~ J, ,~
.. ;

1341 Opg unsubstituted or may have at least one substituent selected from the group consisting of substituents (a), defined above, that is:
hydroxy groups;
straight: and branched chain alkoxy groups containing from 1 t:o 6, preferably from 1 to 3, carbon atoms such as the methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, isopentyloxy, t-pentyl.oxy amd hexyloxy groups . Of these, the methoxy, ethoxy, propoxy and.-isopropoxy groups are preferred:
aliphatic acy7Loxy groups containing from 2 to 6, preferably from 2 to 4, carbon atoms such as the acetoxy, propi~onyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy and hexanoyl.oxy gi:oups, of which the acetoxy, propionyloxy, butyryloxy and isobutyryloxy groups are preferred aliphatic acyl. groups containing from 1 to 6.
preferably from 1 to 4, carbon atoms such as the formyl, acetyl., propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and hexanoyl groups, of which. the f:ormyl, acetyl, propionyl, butyryl and isobutyryl groups are preferred;
carboxy grouper;
alkoxycarbonyl. groups containing a total of from 2 to 6, preferably from 2 to 4, carbon atoms (i.e. the alkoxy part has from 1 to 5, preferably from 1 to 3, carbon atoms), such as the methoxycarbonyl, ethoxy-carbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl., isobutoxycarbonyl, t-butoxycarbonyl 1341 pp9 and pen~tyloxycarbonyl groups, of which the methoxy-carbony:l, eth~~xycarbonyl, propoxycarbonyl and isopropoxycarbonyl groups are preferred;
sulfo groups;
amino groups;
aliphatic acy:Lamino groups containing from 2 to 6, preferably from 2 to 4, carbon atoms such as acetoami.do, propionamido. butyramido, isobutyramido, valerami.do, i~aovaleramido and pivaloylamino groups, of which the acetoamido. propionamido, butyramido and isobutyramido groups are preferred; and mono- arid di-alkyl-substituted amino groups in which the or each alkyl group contains from 1 to 6, preferably from 1 to 4, carbon atoms such as the methylamino, ethylamino, propylamino, isopropyl-amino, butylannino, isobutylamino, dimethylamino, diethyla~mino, dipropylamino, diisopropylamino, pentylamino and hexylamino groups, of which the methylamino. ifimethylamino, ethylamino, propylamino, isopropylamino, butylamino and isobutylamino groups are preferred..
Where R4 reprE~sents an aralkyl group, this has from 1 to 4 alkyl groups in the alkyl part and from 6 to 10 carbon atoms in the aryl part. Examples of such groups include the' ben2yl, phenethyl, 1-phenylethyl, 1-phenylprop~yl, 2--phenylpropyl, 3-phenylpropyl, 4-phenylbutyl, 1-naphthylmethyl and 2-naphthylmethyl groups. These groups may be unsubstituted or may have at least one subst;ituent on the aryl part selected from the group consisting of substituents (c),~defined above. Examaples c>f the groups which may be included in substituents (c) are as exemplified in relation to the ~34f ~~9 same groups included in substituents (a), as well as C1 - C6 alkyl groups, such as those exemplified in relation to the alkyl groups which may be represented by R4, nitro groups and cyano groups, especially alkoxy groups, amino groups and mono- and di- alkylamino groups. Examples of such groups include the benzyl, p-methoxybenzyl, p-aminobenzyl, p-methylaminobenzyl and p-dimethylaminobenzyl groups.
Where Rq~ represents an aliphatic acyl group, this may contain from 7L to b, preferably from 1 to 4, carbon atoms, and examples include the formyl, acetyl, propionyl, butyryll, isobutyryl, valeryl, isovaleryl, pivaloyl and hexanoyl groups, of which the formyl, acetyl, prop~ionyl, butyryl and isobutyryl groups are preferred. These groups may be unsubstituted or may have at least one substituent selected from the group consisting of substituents (a), defined and exemplified above.
Where R2 represents said group of formula (II) or said group of formula (IV), R5 and R10 respectively, may each represent a hydrogen atom or an alkyl group containing from 1 to 6, preferably from 1 to 3, carbon atoms. Examples of such groups include the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, t-pentyl, hexyl and 1,3-dimethylbutyl groups. Of these, the methyl, ethyl, propyl and isopropyl groups a.re preferred. R5 may also represent such an alkyl group having at least one substituent selected from the group consisting of substituents (b), def fined above, i . e~.
hydroxy groups;

straight and branched chain alkoxy groups containing from 1 to 6, preferably from 1 to 3, carbon atoms 1 341 009 ' such_as the me!thoxy, ethoxy, propoxy, isopropoxy, butoxy, isobut:oxy, pentyloxy, isopentyloxy, t-pentyloxy and hexyloxy groups. Of these, the methoxy, ethos;y, propoxy and isopropoxy groups are preferred; andl halogen atoms, such as the fluorine, chlorine.
bromine and iodine atoms, of which the fluorine and chlorine atoms, are preferred.
Where R2 represents said group of formula (III), R6 may represent: a hydrogen atom: an alkyl group containing from 1 to 6, preferably from 1 to 3, carbon atoms, such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, t-pentyl, hexyl and 1.3-dimethylbutyl groups, of which the methyl, ethyl, propyl and isopropyl groups are preferred; a substituted alkyl group :having from 1 to 6 carbon atoms, which may be any of the unsubstituted groups exemplified above and in which the substituent is selected from the group consisting of substituents (b), defined and exemplified above; a hyd.coxy group; an alkoxy group containing from 1 to 6, preferably from 1 to 3, carbon atoms, such as the methoxy, ethoxy, propoxy, isopropoxy, butoxy.
isobutoxy, pentyloxy, isopentyloxy, t-pentyloxy and hexyloxy groups, of which the methoxy, ethoxy, propoxy and isopropo:Ky groups are preferred; or an alkoxy group containing from 1 to 6, preferably from 1 to 3, carbon atoms and having at least one fluorine substituent, such as the fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-f luoroetho:Ky, 2-f luoroethoxy. 2 . 2-dif luoroethoxy, 2,2,2-trifluoroethoxy. 3-fluoropropoxy. 4-fluorobutoxy, 5-f luoropent!tloxy. 6-f luorohexyloxy, 3 , 3-dif luoro-propoxy, 3.3,3-trifluoropropoxy, 4,4-difluorobutoxy and 4.4.4-trifluorobutoxy groups, of which thd fluoro-methoxy, dif:luoromethoxy, trifluoromethoxy, 1-fluoro-ethoxy. 2-fluoroethoxy. 2.2-difluoroethoxy and 1341 00~

2,2,2-trifluoroetlzoxy groups are preferred.
Where R'~ represents said group of formula (III) and R~ represents said group of formula R8R9N-(CH2)9,-, R8 and R9 may be the same or different ar,~d each represents: a hydrogen atom; an alkyl group containing l:rom 1 to 6, preferably from 1 to 3, carbon atoms, such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, t-pentyl, hexyl and 1,3-dimE~thylbutyl groups, of which the methyl, ethyl, propyl and isopropyl groups are preferred; or an aralkyl group, which may be as defined and exemplified above in relation to the aralkyl groups which may be represented by R4, and may optionally be substituted by at least one substituent selected from the group consisting of subs;tituents (c), defined. and exemplified above, and preferably with a C1 - C6 alkoxy group, an amino group, or a mono- or di-(C1 - C6) alkyl-amino group such a,s the benzyl, g-methoxybenzyl, p-aminobenzyl, p-methylaminobenzyl and p-dimethyl-aminobenzyl groups.
Alternatively, R~ may represent: a hydroxy group;
or an alkoxy group containing from 1 to 6, preferably from 1 to 3, carbon atoms such as the methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, isopentyloxy, t-pentyloxy and hexyloxy groups, of which the methoxy, ethoxy, propoxy and isopropoxy groups are preferred.
In the group of formula (V), Z may be an oxygen atom or a sulfur .atom; where it is an oxygen atom, the group is the morph~olino group; where it is a sulfur atom, the group is a thiomorpholino (i.e. perhydro-1,4-thiazin-4-yl) group.
Of the c~~mpounds of formula (I), the preferred 1 34i 009 compounds are those in which R2 represents:
a group of formula (II):
. _r.
I I (II) \ X
A (R5)m (in which R~4, R5, A and m are as deffined above);
a group of :Formula (IIIa):
(CH2)n I i (IIIa) 130- ~ N-\ X
B'R6 (in which: R6 represents a hydrogen atom or an alkyl group havin~I from 1 to 3 carbon atoms; B' represents a methylene group or an ethylene group; and n is as defined above);
a group of formu la (IIIb):
lZ8 ( CH2 ) n \ I I
N-(C1H2)q-~ N- (IIIb) / \ X
IR9 B' R6 (in which R~'. Ra, R9, B', n and g are as defined above);

a group of formula (IIIc):

,~ 11 \
I I (IIIc) ~ 1V-/ \ /
F~ 12 (in which: R11 and R12 are independently selected from the group consisting of hydroxy groups and alkoxy groups having from 1 to 3 carbon atoms):
a group of formula (IVa):

. // \ /' I II
(IVa) -N
(in which R10 is as defined above); or a group of formula (V):
._.
/ \
Z N- (V) \ /
(in which Z 'is as defined above).
We also prefer those compounds of formula (I) in which R1 represents a dif luoromethoxy group or a trifluoromethoxy group, and especially those in which R1 represents a di:Eluoromethoxy group or a trifluoromethoxy group and R2 represents a group of formula (II),. (IIIa), (IIIb). (IIIc), (IVa) or (V), as deffined abovf~, both where R3 represents a hydrogen atom and.where it represents an amino group.
The compounds of the invention contain one carboxy group at they 3-po:~ition of the quinoline ring. This carboxy group may form esters, amides and salts.
Where tb:e carboxy group is esterified, the nature of the resulting estE~r is not critical to the present invention. In principle, the compounds of the invention, being carboxylic acids, will form esters with any ester-forming alcohol and all such esters form part of the present invention. However, where the esters are to be employed for therapeutic purposes, it is, of course, necessary that the resulting esters should be pharmaceutically acceptable, which, as is well understood in the art, means that the esters should not have reduced activity (or unacceptably reduced activity) and should not have increased toxicity (or unacceptably increased toxicity) as compared with the free acid.
However, where the ester is to be employed for other purposes, for example as an intermediate in the preparation of other compounds, even this criterion does not apply.
Examples of such esters include: C1 - C6, more preferably C;L - C4, alkyl esters, for example the methyl, ethy:L, propyl, isopropyl, butyl, isobutyl, sec-butyl, t--butyl, pentyl and hexyl esters; aralkyl (including d:iarylalkyl) esters, such as the benzyl, p-nitrobenzy:l and benzhydryl esters; lower aliphatic acyloxyalkyl groups, such as the acetoxymethyl or pivaloyloxymE:thyl groups: alkoxycarbonylalkyl esters, in which the alkoxy a:nd alkyl parts are both C1 - C4, especially a7lkoxyc,arbonylmethyl and 1-(alkoxycarbonyl)-ethyl esters, such as the ethoxycarbonylmethyl and t-butoxycarbonylmethyl esters; alkoxycarbonyloxyalkyl esters in which the alkoxy and alkyl parts are both Cl - C4,_especially the 1- and 2- (alkoxycarbonyl-oxy)ethyl esters, such as the 1-(ethoxycarbonyloxy)-ethyl, 1-(isopropoxycarbonyloxy)ethyl, 2-methoxy-carbonyloxyethyl, 2-ethoxycarbonyloxyethyl and 2-t-butoxycarbonyloxyethyl esters; N,N-di-substituted aminocarbonylalkyl esters, in which the alkyl group is Cl - C6, pr~epferably C1 - C4, and the substituenta on the amino group are preferably C1 - C4 alkyl groups such as the N,N-dimethylamino-carbonylmetlzyl esters: and other specific esters, such as the phthalidyl, substituted phthalidyl, phenacyl, substituted phenacyl (e. g. p-nitrophenacyl), (5-phenyl-2-oxo-1,3-d:ioxole;n-4-yl)methyl and (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esters.
Likewise, where the carboxy group has formed an amide, the precise nature of the amide is not critical, provided that, where the amide is to be used for therapeutic purposes, the resulting amide is pharmaceutically acceptable. Accordingly, the carboxy group can beg replaced by a carbamoyl group or a substituted carbatnoyl group, preferably an alkylcarbamoyl or dialkylcarbamoyl group in which the or each alkyl croup its a C1 - C3 alkyl group (e.g. as defined above in i:elation to R4), for example a methylcarbamoyl, E~thylcarbamoyl, dimethylcarbamoyl or diethylcarba.moyl croup.
The carboxy gt:oup may also form salts with appropriate bases. The nature of such salts is likewise not critical, provided that, where they are to be used for therapeutic purposes, the salts are pharmaceutically acceptable. Examples of salts with bases include: salts with metals, especially alkali metals and alkaline earth metals, such as lithium, sodium, potassium, calcium and magnesium, and other metals, such as manganese, iron and aluminum; the ammonium salt; salts with organic amines, such as cycl.ohexy:lamine, diisopropylamine or triethyl-amine; and salts with basic amino acids, such as lysine or arginine.
The compounds of the invention contain a basic nitrogen atom and hence can also form acid addition salts. The natures of such salts is likewise not critical to the present invention, except that, where the salts are to be used for therapeutic purposes, they must be pharmaceutically acceptable. A wide variety of acids may be employed to form such salts and representative examples of such acids include: mineral acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, metaphosphoric acid, nitric acid or sulfuric acid: organic carboxylic acids, such as acetic acid, oxalic acid, tartaric acid, citric acid, benzoic acid, glycolic acid, gluconic acid, glucuronic acid, succinic acid, malefic acid or fumaric acid; and organic sulfonic acids, such as methane-sulfonic acid, ethanesulfonic acid, benzenesulfonic acid or p-tolueneesulfonic acid. Such acid addition salts may be prepared by conventional methods.
The compounds ~of the invention may also exist in the form of hydrates a;nd these likewise form part of the present invention.
Specific examples of compounds of the invention are given by the foregoing formula (I), in which the substituents are ass defined in the following Table 1.
In the Table, the iEollowing abbreviations are used:
Ac acetyl Azp perhydroazepinyl Azt azetidinyl Bz benzyl ~34~0~9 Diz - perhydro-1,4-diazepinyl (= homopiperazinyl) Et ethyl Etc ethoxycarbonyl Imid imidazolyl Me methyl Mor morpholino Pip piperidyl Piz piperazinyl iPr isopropyl Pyrd pyrrolidinyl Sfo sulfo Thz perhydro-1,4-thiazin-4-yl (= thiomorpholino) 1341 OOg . TABLE 1 Cpd R1 R3 R2 No.
1 OCHF2 H 1-Pi2 2 OCHF2 H 3-Me-1-Piz 3 OCHF2 H 3,5-diMe-1-Piz 4 OCHF2 H 2,5-diMe-1-Pi2 5 OCHF2 H ~ 4-Me-1-Pi2 6 OCHF2 H 3,4-diMe-1-Piz 7 OCHF2 H 3,4,5-triMe-1-Piz 8 OCHF2 H 4-Et-1-Piz , 9 OCHF2 H 4-{2-HOEt)-1-Pi2 10 OCHF2 H 4-(2-MeOEt)-1-Piz 11 OCHF2 H 4-(2-AcOEt)-1-Pi2 12 OCHF2 H 4-(2-NH2Et)-1-Pi2 13 OCHF2 H 4-(2-NMe2Et)-1-Piz 14 OCHF2 H 4-(4-NH2Bz)-1-Pi2 15 OCHF2 H 4-HCO-1-Piz 16 OCHF2 H 4-Ac-1-Pi2 17 OCHF2 H 4-(AcMe)-1-Piz 18 OCHF2 H 4-(EtcMe)-1-Pi2 19 OCHF2 H 4-(,SfoMe)-1-Piz 20 OCHF2 H 1-Di2 21 OCHF2 H 4-Me-1-Diz 22 OCHF2 H 3-oxo-1-Piz 23 OCHF2 H 4-Me-3-oxo-1-Pi2 24 OCHF2 H 3-HO-1-Pyrd 25 OCHF2 H 4-HO-1-Pip 26 OCHF2 H 3,4-diHO-1-Pyrd TABLE 1 (cont) Cpd R1 R3 R2 No.

27 OCHF2 H 3-HO-4-Me0-1-Pyrd 28 OCHF2 H 3-NH2-1-Azt 29 OCHF2 H 3-NHMe-1-Azt 30 OCHF2 H 3-NMe2-1-Azt 31 OCHF2 H 3-(NH2Me)-1-Azt 32 OCHF2 H 3-[(NHEt)Me]-1-Azt 33 OCHF2 H 3-[(NMe2)Me]-1-Azt 34 OCHF2 H 3-NH2-1-Pyrd , 35 OCHF2 H 3-NHEt-1-Pyrd 36 OCHF2 H 3-NMe2-1-Pyrd 37 OCHF2 H 3-(NH2Me)-1-Pyrd 38 OCHF2 H 3-[(NHMe)Me]-1-Pyrd 39 OCHF2 H 3-[(NHEt)Me]-1-Pyrd 40 OCHF2 H 3-[(NMe2)Me]-1-Pyrd 41 OCHF2 H 3-NH2-4-Me-1-Pyrd 42 OCHF2 H 3-NH2-4-HO-1-Pyrd 43 OCHF2 H 3-NH2-4-Me0-1-Pyrd 44 OCHF2 H 3-NH2-4-Et0-1-Pyrd 45 OCHF2 H 4-NH2-1-Pip 46 OCHF2 H 4-NHMe-1-Pip 47 OCHF2 H 4-NMe2-1-Pip 48 OCHF2 H 3-NH2-1-Pip 49 OCHF2 H 3-NHMe-1-Pip 50 OCHF2 H 3-NH2-1-Azp 51 OCHF2 H 3-NH2-3-Me-1-Pyrd 52 OCHF2 H 1-Imid 53 OCHF2 H 4-Me-1-Imid 54 OCHF2 H Mor . TABLE 1 (cont) Cpd R1 R3 R2 No.

55 OCHF2 H Thz 56 OCHF2 H 3-Et-1-Piz 57 OCHFZ H 3,3-diMe-1-Piz 58 OCHF2 H 3-iPr-1-Piz 59 OCHF2 H 3-(MeOMe)-1-Piz 60 OCHF2 H 4-(HCOMe)-3-Me-1-Piz 61 OCHF2 H 3,5-di(CH2F)-1-Pi2 62 OCHF2 H 4-NH2-1-Piz , 63 OCHF2 H 4-HO-i-Piz 64 OCHF2 H 4-(2-HOEt)-3-Me-1-Piz 65 OCHF2 H 4-(2-MeOEt)-3-Me-1-Piz 66 OCHF2 H 3-CH2F-1-Piz 67 OCHF2 H 4-NH2-3-Me-1-Piz 68 OCHF2 H 4-(HCOMe)-1-Piz 69 OCHF2 H 4-HO-3-Me-1-Piz 70 OCHF2 H 4-(AcMe)-3-Me-1-Piz 71 OCHF2 H 3-Me-1-Diz 72 OCHF2 H 3-NH2-4-(MeOMe)-1-Pyrd 73 OCHF2 H 3-NH2-4-(CF3CH20)-1-Pyrd 74 OCHF2 NH', 1-Piz 75 OCHF2 NH2, 3-Me-1-Piz 76 OCHF2 NH2, 3,5-diMe-1-Piz 77 OCHF2 NH2, 2,5-diMe-1-Piz 78 OCHF2 NH2 4-Me-1-Piz 79 OCHF2 NH2 3,4-diMe-1-Piz 80 OCHF2 NH2 3,4,5-triMe-1-Piz 81 OCHF2 NH2 4-Et-1-Pi.z 82 OCHF2 NH2 4-(2-HOEt)-1-Piz, TABLE 1 tcont) Cpd R1 R3 R2 No.

83 OCHF2 NH;Z 4-(2-MeOEt)-1-Piz 84 OCHF2 NH;Z 4-(2-AcOEt)-1-Piz 85 OCHF2 NH,Z 4-(2-NH2Et)-1-Piz 86 OCHF2 NH,~ 4-(2-NMe2Et)-1-Piz 87 OCHF2 NH,~ 4-(4-NH2Bz)-1-Piz 88 OCHF2 NH,~ 4-HCO-1-Piz 89 OCHF2 NH,~ 4-Ac-1-Piz 90 OCHF2 NH., 4-(Ache)-1-Piz , 91 OCHF2 NH,~ 4-{EtcMe)-1-Piz 92 OCHF2 NH~~ 4-(SfoMe)-1-Piz 93 OCHF2 NH~~ 1-Diz 94 OCHF2 NHS, 4-Me-1-Diz 95 OCHF2 NHS, 3-oxo-1-Piz 96 OCHF NH 4-Me-3-oxo-1-Piz , 97 2 S 3-HO-1-Pyrd OCHF2 NHS, 98 OCHF2 NH2, 4-HO-1-Pip 99 OCHF2 NHZ, 3,4-diHO-1-Pyrd 100OCHF2 NH2, 3-HO-4-Me0-1-Pyrd 101OCHF2 NH2 3-NH2-1-Azt 102OCHF2 NH2 3-NHMe-1-Azt 103OCHF2 NH2 3-NMe2-1-Azt 104OCHF2 NH2 3-{NH2Me)-1-Azt 105OCHF2 NH2 3-[(NHEt)Me]-1-Azt 106OCHF2 NH2 3-[{NMe2)MeJ-1-Azt 107OCHF2 NH2 3-NH2-1-Pyrd 108OCHF2 NH2 3-NHEt-1-Pyrd 109OCHF2 NH2 3-NMe2-1-Pyrd 110OCHF2 NH2 3-(NH2Me)-1-Pyrd.

TABLE 1 (cont) Cpd R1 R3 R2 No.
111 OCHF2 NH,2 3-[(NHMe)Me]-1-Pyrd 112 OCHF2 NH;Z 3-[(NHEt)Me]-1-Pyrd 113 OCHF2 NH;Z 3-[(NMe2)Me]-1-Pyrd 114 OCHF2 NH;Z 3-NH2-4-Me-1-Pyrd 115 OCHF2 NH,~ 3-NH2-4-HO-1-Pyrd 116 OCHF2 NH,~ 3-NH2-4-Me0-1-Pyrd 117 OCHF2 NH,~ 3-NH2-4-Et0-1-Pyrd 118 OCHF2 NH,~ 4-NH2-1-Pip , 119 OCHF2 NH's 4-NHMe-1-Pip 120 OCHF2 NH~~ 4-NMe2-1-Pip i21 OCHF2 NH~~ 3-NH2-1-Pip 122 OCHF2 NH~~ 3-NHMe-1-Pip 123 OCHF2 NHS, 3-NH2-1-Azp 124 OCHF2 NHS, 3-NH2-3-Me-1-Pyrd 125 OCHF2 NHS, 1-Imid 126 OCHF2 NH2, 4-Me-1-Imid 127 OCHF2 NHZ, Mor 128 OCHF2 NH2, Thz 129 OCHF2 NH2 3-Et-1-Piz 130 OCHF2 NH2 3,3-diMe-1-Piz 131 OCHF2 NH2 3-iPr-1-Piz 132 OCHF2 NH2 3-(MeOMe)-1-Piz 133 OCHF2 NH2 4-(HCOMe)-3-Me-1-Piz - ,134 OCHF2 NH2 3,5-di(CH2F)-1-Piz 135 OCHF2 NH2 4-NH2-1-Piz 136 OCHF2 NH2 4-HO-1-Piz 137 OCHF2 NH2 4-(2-HOEt)-3-Me-1-Piz 138 OCHF2 NH2 4-(2-MeOEt)-3-Me~l-Piz TABLE 1 (cont) Cpd R1 R3 R2 No.
139 OCHF2 NHS, 3-CH2F-1-Piz 140 OCHF2 NHS, 4-NH2-3-Me-1-Piz 141 OCHF2 NHS, 4-(HCOMe)-1-Piz 142 OCHF NH 4-HO-3-Me-1-Piz , 143 OCHF2 NHS, 4-(AcMe)-3-Me-1-Piz 144 OCHF2 NH2, 3-Me-1-Diz 145 OCHF2 NH2, 3-NH2-4-(MeOMe)-1-Pyrd 146 OCHF2 NH2, 3-NH2-4-(CF3CH20)-1-Pyrd , 147 OCF3 H 1-Piz 148 OCF3 H 3-Me-1-Piz 149 OCF3 H 3,5-diMe-1-Piz 150 OCF3 H 2,5-diMe-1-Piz 151 OCF3 H 3,3-diMe-1-Piz 152 OCF3 H 4-Me-1-Piz 153 OCF3 H 3,4-diMe-1-Piz 154 OCF3 H 4-Et-1-Piz 155 OCF3 H 4-(2-HOEt)-1-Pi2 156 OCF3 H 4-(2-MeOEt)-1-Piz 157 OCF3 H 4-(2-AcOEt)-1-Pi2 158 OCF3 H 4-(2-NH2Et)-1-Piz 159 OCF3 H 4-(4-NH2Bz)-1-Piz 160 OCF3 H 4-HCO-1-Piz 161 OCF3 H 4-Ac-1-Piz 162 OCF3 H 4-(AcMe)-1-Piz 163 OCF3 H 4-(HOOCMe)-1-Piz 164 OCF3 H 4-(EtcMe)-1-Piz 165 OCF3 H 1-Di2 166 OCF3 H 4-Me-1-Diz ' ~34~ X49 TABLE 1 (cont) Cpd R1 R3 R2 No.
167 OCF3 H 3-oxo-1-Piz 168 OCF3 H 4-Me-3-oxo-1-Piz 169 OCF3 H 3-HO-1-Azt 170 OCF3 H 3-HO-1-Pyrd 171 OCF3 H 3-HO-4-Me0-1-Pyrd 172 OCF3 H 3.4-diMeO-1-Pyrd 173 OCF3 H 3-NH2-1-Azt 174 OCF3 H 3-NHMe-1-Azt , 175 OCF3 H 3-NHEt-1-Azt 176 OCF3 H 3-(NH2Me)-1-Azt 177 OCF3 H 3-[(NHMe)Me]-1-A2t 178 OCF3 H 3-[(NMe2)Me]-1-A2t 179 OCF3 H 3-NH2-1-Pyrd 180 OCF3 H 3-NHMe-1-Pyrd 181 OCF3 H 3-NMe2-1-Pyrd 182 OCF3 H 3-(NH2Me)-1-Pyrd 183 OCF3 H 3-[(NHMe)Me]-1-Pyrd 184 OCF3 H 3-[(NHEt)Me]-1-Pyrd 185 OCF3 H 3-[(NMe2)Me]-1-Pyrd 186 OCF3 H 3-NH2-4-Me-1-Pyrd 187 OCF3 H 3-NH2-4-HO-1-Pyrd 188 OCF3 H 3-NH2-4-Me0-1-Pyrd 189 OCF3 H 3-NH2-4-Et0-1-Pyrd 190 OCF3 H 4-NH2-1-Pip 191 OCF3 H 4-NHMe-1-Pip 192 OCF3 H 3-NH2-1-Pip 193 OCF3 H 3-NHMe-1-Pip 194 OCF3 H 3-NMe2-1-Pip ' ~ 34 ~ 009 TABLE 1 (cont) Cpd R1 R3 R2 No.
195 OCF3 H 3-NH2-1-Azp 196 OCF3 H 3-NH2-3-Me-1-Pyrd 197 OCF3 H 1-Imid 198 OCF3 H 4-Me-1-Imid 199 OCF3 H Mot 200 OCF3 H Thz 201 OCH2F H 3,3-diMe-1-Piz 202 OCH2F H 4-Me-1-Diz _ 203 OCH2F H 1-P1z 204 OCH2F H 1-Diz 205 OCH2F H 3-NH2-1-Pyrd 206 OCH2F H 3-Me-1-Piz 207 OCH2F H 4-Me-1-Piz 208 OCH2F H 3-NH2-4-Me-1-Pyrd 209 OCH2F H 3,5-diMe-1-Piz 210 OCH2F H 3,4-diMe-1-Piz 211 OCH2F H 3-NHMe-1-Pyrd 212 OCH2F H 3-NMe2-1-Pyrd 213 OCF3 NH2 1-Piz 214 OCF3 NH2 3-Me-1-Piz 215 OCF3 NH2 3,5-diMe-1-Piz 216 OCF3 NH2 2,5-diMe-1-Piz 217 OCF3 NH2 3,3-diMe-1-Piz 218 OCF3 NH2 4-Me-1-Piz 219 OCF3 NH2 3,4-diMe-1-Piz 220 OCF3 NH2 4-Et-1-P12 221 OCF3 NH2 4-(2-HOEt)-1-Piz 222 OCF3 NH2 4-(2-MeOEt)-1-Pig ~3410~9 TABLE 1 (cont) Cpd R1 R3 R2 No.
223 OCF3 NHS, 4-(2-AcOEt)-1-Piz 224 OCF3 NHS, 4-(2-NH2Et)-1-Piz 225 OCF3 NHS, 4-(4-NH2Bz)-1-Piz 226 OCF3 NH2, 4-HCO-1-Piz 227 OCF3 NH2, 4-Ac-1-Piz 228 OCF3 NH2 4-(AcMe)-1-Piz 229 OCF3 NH2 4-(HOOCMe)-1-Piz 230 OCF3 NH2 4-(EtcMe)-1-Piz 231 OCF3 NH2 1-Di2 232 OCF3 NH2 4-Me-1-Diz 233 OCF3 NH2 3-oxo-1-Piz 234 OCF3 NH2 4-Me-3-oxo-1-Pi2 235 OCF3 NH2 3-HO-1-Azt 236 OCF3 NH2 3-HO-1-Pyrd 237 OCF3 NH2 3-HO-4-Me0-1-Pyrd 238 OCF3 NH2 3,4-diMeO-1-Pyrd 239 OCF3 NH2 3-NH2-1-Azt - 240 OCF3 NH2 3-NHMe-1-Azt 241 OCF3 NH2 3-NHEt-1-Azt 242 OCF3 NH2 3-[(NH2)Me]-1-Azt 243 OCF3 NH2 3-(NHMeMe)-1-Azt 244 OCF3 NH2 3-[(NMe2)MeJ-1-Azt 245 OCF3 NH2 3-NH2-1-Pyrd 246 OCF3 NH2 3-NHMe-1-Pyrd 247 OCF3 NH2 3-NMe2-1-Pyrd 248 OCF3 NH2 3-[(NH2)Me]-1-Pyrd 249 OCF3 NH2 3-[(NHMe)MeJ-1-Pyrd 250 OCF3 NH2 3-[(NHEt)Me]-1-Pyrd - TABLE 1 (cont) Cpd R1 R3 R2 No.
251 OCF3 NH2 3-[(NMe2)Me]-1-Pyrd 252 OCF3 NH2 3-NH2-4-Me-1-Pyrd 253 OCF3 NH2 3-NH2-4-HO-1-Pytd 254 OCF3 NH2 3-NH2-4-Me0-1-Pyrd 255 OCF3 NH2 3-NH2-4-Et0-1-Pyrd y 256 OCF3 NH2 4-NH2-1-Pip 257 OCF3 NH 4-NHMe-1-Pip 258 OCF3 , 3-NH2-1-Pip , NH,2 259 OCF3 NH,2 3-NHMe-1-Pip 260 OCF3 NH;Z 3-NMe2-1-Pip 261 OCF3 NH;Z 3-NH2-1-Azp 262 OCF3 NH;Z 3-NH2-3-Me-1-Pyrd 263 OCF3 NH;Z 1-Imid 264 OCF3 NH;Z 4-Me-1-Imid 2 6 5 OCF 3 NH;Z Mo r 2 6 6 OCF 3 NH,~ Thz 267 OCH2F NH,~ 3,3-diMe-i-Piz 268 OCH2F NH,~ 4-Me-1-Diz 269 OCH2F NH,~ 1-Piz 270 OCH2F NH,~ 1-Diz 271 OCH2F NH,~ 3-NH2-1-Pyrd 272 OCH2F NH,~ 3-Me-1-Piz 273 OCH2F NH.~ 4-Me-1-Pi2 - 274 OCH2F NH.~ 3-NH2-4-Me-1-Pyrd 275 OCH2F NH.~ 3,5-diMe-1-Piz 276 OCH2F NH~~ 3,4-diMe-1-Piz 277 OCH2F NH., 3-NHMe-1-Pyrd 278 OCH NH 3-NMe2-1-Pyrd ' F ~

2 ~

1 ~4~ a~9 TABLE 1 (cont) Cpd R1 g3 R2 No.
279 OCHF2 H 3-(HOMe)-1-Piz 280 OCHF2 NH~~ 3-(HOMe)-1-Piz 281 OCHF2 H 4-(SfoMe)-3-Me-1-Piz 282 OCHF2 NH~~ 4-(SfoMe)-3-Me-1-Piz 283 OCHF2 H 4-(AcEt)-1-Piz 284 OCHF2 NHS, 4-(AcEt)-1-Pi2 285 OCHF2 H 4-(AcEt)-3-Me-1-Piz 286 OCHF2 NHS, 4-(AcEt)-3-Me-1-Piz Of the compounds listed above, the following are preferred, that is to say Compounds No. 1, 2, 3, 5, 24, 34, 39, 41. 43. 45, 46, 48, 56, 59, 72, 74, 75, 76, 78, 79, 82, 93, 94, 97, 107, 114. 116, 129, 131. 133, 136, 137, 139, 141. 142, 144. 179. 186, 202, 203, 204, 205, 206, 207, 208, 209, 213. 214, 245, 252, 268, 269. 270, 271. 272, 273. 274', 275, 279, 280, 281. 282. 283, 284, 285 and 286, and the following are the more preferred, that is to say Compounds No. 1. 2, 3. 5, 34, 39, 43.
45, 46, 48, !56, 59, 72, 74, 75, 76, 78, 79, 82, 93, 94.
107, 116, 12'x. 131, 133, 136, 137, 139. 141, 142, 144, 179 and 284.
The following are the most preferred:
1. 1-Cyclopropyl-8-difluoromethoxy-6-fluoro-7-(1-piperazinyl)--1.4-dihydro-4-oxoquinoline-3-carboxylic acid; ' 2. 1-Cyclo~propyl-8-difluoromethoxy-6-fluoro-7-(3-methyl-1-pi~perazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;
3. 1-Cyclopropyl-8-difluoromethoxy-6-fluoro-7-(3,5-dimethyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid:
34. 1-Cyclopropya-8-difluoromethoxy-6-fluoro-7-(3-amino-1-pyrrolidinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;
74. 5-Amino-1-cyc:lopropyl-8-difluoromethoxy-6-fluoro-7-(1-piperazinyl)--1,4-dihydro-4-oxoquinoline-3-carboxylic acid;
75. 5-Amino-1-cyclopropyl-8-difluoromethoxy-6-fluoro-7-(3-methyl-1-pipe~razinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;
76. 5-Amino-1-cyclopropyl-8-difluoromethoxy-6-fluoro-7-(3,5-dimethyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;
78. 5-Amino-1-cyclopropyl-8-difluoromethoxy-6-fluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;
93. 5-Amino-1-cyclopropyl-8-difluotomethoxy-6-fluoro-7-(1-homopiperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic arid;
107. 5-Amino-1-cyclopropyl-8-difluoromethoxy-6-fluoro-7-(3-amino-1--pyrrolidinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid; ' 139. 5-Amino-1-cyclopropyl-8-difluoromethoxy-6-fluoro-7-(3-fluoromethyl-1-piperazinyl)-1,4-dihydro-4-oxo-quinoline-3--carboxylic acid;
144. 5-Amino-1-cyclopropyl-8-difluoromethoxy-6-fluoro-7-(3-methyl--1-homo piperazinyl)-1,4-dihydro-4-oxo-quinoline-3--carbo:Kylic acid.
Also preferred are pharmaceutically acceptable salts, esters and amides, more preferably salts and esters, and most preferably hydrochlorides and methane-sulfonates, of then above preferred and most preferred Compounds.
In general germs, the compounds of the present invention may be prepared by reacting a compound of formula (VI):

ii \ // \ / \ /
C'. C C
II H
C' C CH (VI ) / \\ / \ /
X C N

(in which R1 and R3 are as defined above; X
represents a halogen atom and is preferably a fluorine atom; and R13 represents a hydrogen atom or a carboxy-pro tecting group) or an active derivative or equivalent thereof with a compound of formula (VII):

R2-H (VII) 1341 p~9 (in which R2 is as defined above) or an active derivative or equivalent thereof, and, if necessary, subjecting the product to any one or more of the reactions: ~deprotection, salification, esterification and amidation.
R13 may represent any carboxy-protecting group known in organic chemistry for use with Lhis type of compound and may be incorporated into and (if desired) removed from the compound by well known methods which require no ~alabor.ation here. However, R13 is preferably a hydrogen atom or a C1 - C6, preferably C1 - C4, alkyl group, for example a methyl, ethyl, propyl, isopropyl, butyl, t-butyl, or hexyl group, most preferably a hydrogen atom, a methyl group or an ethyl group.
Alternatively, R13 may represent a boron difluoride I:BF2) group. In this case, the boron difluoride croup will normally form a coordinate bond with the oxygen a tom at the 4-position of the quinoline ring.
A preferred method of preparing the compounds of the invention is. illustrated in more detail by Reaction Scheme A:

Reaction Scheme A, R 3 0 . 1;3 R 0 F ~ , COOK F / COOR~3 -Step A1 X ' R CR 2 - H7 RZ ~ H
Rl IYII) Rl itlI) tlIIII) + HBF4 Step A2 or 6F3 ,6F2 8F2 R 3 Of ~0. R3 0~~ '0 F ~ Step A ~' F C
'0 (R2_H] '0 v X ~ ( I I ) RZ H~
R~
fIX) (X) Step ~A~ Step A 5 ~~basic [agueous agueous al cohol]
alcohol]
_ R3 0 R3 0 Step A6 RZ [base] RZ .8F2X
A~ ~ R~ Q
(I ) (Xll In the above formulae, Rl, R2, R3, X and R13 are as defined above.
In the reactions shown in the above reaction scheme, the compounds of formula (I) of the present invention can be prepared by reacting a compound of formula (VI) or its boron difluoride chelate of formula (IX) with an amine compound of formula (VII) in Steps A1 and A3, respectively. The reaction may be effected in the presence or absence of an acid binding agent and in the presence or absence of a solvent.
The molar ratio of the compound of formula (VI) or (IX) to the amine of formula (VII) is not critical, although we generally prefer to employ equimolar amounts of the two reagents or a molar excess of the amine.
Where a solvent is employed, its nature is not particularly critical, provided that it has no adverse effect on the reaction. Examples of suitable solvents include: aprotic polar solvents, especially sulfoxides, such as dimethyl esulfoxide, or amides, such as dimethylfornnamide, hexamethylphosphoric triamide or dimethylacet;amide: however, other solvents may also be used, incluiiing: l~cetones, such as acetone or methyl ethyl ketone; ethers, such as diethyl ether, tetrahydrofuran or dioxane; esters, such as ethyl acetate; alc:ohols,, such as methanol, ethanol, propanol, isopropanol or butanol; and nitriles, such as acetonitrilE~. Of these, the aprotic polar solvents are preferred.
Where an acid binding agent is employed, its nature is likewise not particularly critical, provided that it has no adverse efi'ect on the reaction and'that it is capable of t~indin<t to, and hence effectively removing from the reaction" the acid produced in the course of the reaction. Examples of suitable acid binding agents include: tertiary amines, such as 1,8-diazabicyclo-[5.4.0]-7-u:ndecene, 1,5-diazabicyclo[4.3.0]-5-nonene, triethylami;ne, tributylamine, pyridine, picoline, lutidine or collidine: and inorganic bases, preferably alkali metal carbonates, such as sodium carbonate or potassium carbonate, or alkali metal alkoxides, such as sodium methoxide, sodium ethoxide or potassium t-butoxide. The .amount of acid binding agent employed is preferably equimolar or a molar excess, with respect to the compound of formula (VI) or (IX), more preferably a molar ratio of aaid compound of formula (VI) or (IR) to said acid binding agent of from 1 . 1 to 1 . 5.
However, where once of the afore-mentioned amines is used as acid binding agent, it is preferably employed in a large excess, in which case it may serve both as the acid binding agent and as solvent. The reaction may also proceeii smoothly even when an acid binding agent is not employed because an excess of the amine of formula (VII) can serve a;a the acid binding agent.
The reaction ~aay be carried out over a wide range of temperatures, and the exact reaction temperature is not critical to the invention. However, we generally find it convenient to carry out the reaction at a temperature ranging from 0°C to 200°C.
In the compound of formula (VIII), where R13 represents a~ carboxy-protecting group, this is then removed to prepare the corresponding compound where R13 represents a hydrogen atom. This removal may be effected by well known methods appropriate to the nature of the carboxy-protecting group represented by R13.
After the rea<:tion is complete, the desired compound of the inver,~tion c:an be recovered from the reaction mixture by t.reatme nt in a conventional manner, and, if ' 34~ p~~

desired,-may be further purified by such conventional techniques .as recrystallization or the various chromatography techniques, notably column chromatography.
In the :reactions represented by steps A2 to A6, a chelate of :formula (X) of the desired compound is obtained first. a:nd this is then converted into the BF2X addition product (XI) of the compound of formula (I) or the compound of formula (I) itself by treatment with an aqueous alcohol or a basic aqueous alcohol. The BF2X addition product (XI) of the compound of formula ( I ) is easily converted into the compound ( I ) itself by treatment with a ibase.
Examples of bases which may be employed include:
alkali metal. hydroxides, such as sodium hydroxide or potassium hydroxide; alkali metal carbonates, such as sodium carbonate or potassium carbonate; alkali metal alkoxides, :such as sodium methoxide, sodium ethoxide or potassium t-~butox:lde; and tertiary amines, such as 1,8-diazabic:yclo[5.4.0]-7-undecene, 1,5-diazabicyclo-[4.3.0]-5-nonene. triethylamine or 4-dimethylamino-pyridine.
The compound of formula (I) or its BF2X addition product (XI) may, if desired, be converted into a desired salt. by conventional means.
Conversion of the compound of formula (VI) to the boron difluc~ride <:helate of formula (IX) can be carried out, for example, by reaction with hydrofluoroboric acid or boron trifluori.de by the method described in Japanese Patent Application Kokai (i.e. as laid open to public inspection) No. 6i~290/84.
The compound of formula (I) thus prepared may exist as a mixture of o~>tical isomers due to the presence of an asymmetric carbon atom in the moiety of the compound represented by R2 or as geometric (cis or traps) isomers due to, for example, the presence of two or chore substituent;s on the heterocyclic group represented by RZ. In such a case, individual isomers of the compound may be prepared, if desired, by using as the starting material of formula R2-H (VII) a compound which has been optically resolved or separated in advance to obtain the corresponding optical or geometric isomer of the desired compound (I). Alternatively, a mixture of optical or geometric isomers of the compound (I) may be prepared, and these may be resolved or separated into the individual isomers by conventional techniques.
The compounds of formula (VI) used as starting materials in the ,afore-mentioned reactions can be prepared, for instance, by the following Reaction Scheme B.

~34~ppg React ion Scheme 8:
R3 ~ _ - I

0 ~ CO C~
Step 81 X [SOiCl2]
X XI
R
(XII1 R
(XIII ) Step. 82 Ste 86 P
Et OMgCH (COOR»)2] 14 R
31 0 iNCH= CHCOOR17 R II 17 I R15 (XYII) CCH(COOR )2 R3 0 X X ~ Ii R, ~I CH R14 IXIY) ~-N~
R' ~R 15 Step 83 ~TsOH.HZ 0] (XYIII) R3~ 0 St ep 87 C C HZ COOR17 C~-IrH2J

X ~I F CI -C-COOR17 R~ (XY) II
CH
Ste p 84 X
(AcZ 0/ H C (0 E't)3~ R1 H H--R31 ~ f XIX) IC-C-C~DOR» Ste 85 II p CH [~ ~H2' X ~~ ~ i R~ iDEt ""., Reaction Scheme 8 (cost R3 ~ 0 R3~ 0 F C-C' - COO R» F COOR1~
Step 88 CH [b ase~
X ~l ~ X
1 HH~ 1 R R
(XIX 1 (XX) Step 810 [reduct ion Step B9 ~hyd~olysis~
X

~tep 811 [hydrolysis R3 0 ~COOH
X
A ~
fXXI) In the <~bove formulae:
R1, R3 and 7t are as defined above;
R3 represents hydrogen atom or a vitro (N02) group;
R1~ represents a c:arboxy-protecting group, as illustrated in re7Lation to the groups which may be represented by Rl~l;
X' represents a halogen atom, such as a fluorine, chlorine, bromine or iodine group;
R14 and R15 are the same or different and each represents a,Cl - C6 alkyl group, for example as exemplified above in relation to the alkyl groups which may be represented by R4, or R14 and R15 may, together with the nitrogen atom to which they are attached form a heterocyclic group having from 5 to 6 ring atoms of which 0 or 1 is an additional hetero-atom selected from the group consisting of nitrogen, oxygen and sulfur h~etero-atoms and which is unsubstituted or has one or two oxo substituents on a sulfur hetero-atom, to form a su:lfinyl or sulfonyl group;
Ac represents the acetyl group;
Et represent:~ the ethyl group; and Ts represents the ~e-tosyl (p-toluenesulfonyl) group.
The reaction conditions and treatment after completion oi: the reaction in each Step are described in more detail i.n the following Preparations. Of course, the details c>f reaction conditions etc given in these Preparations are merely by way of example and it will be appreciated that these well known reactions may be conducted in a variety of different ways.
In Step B8, examples of suitable bases include:
alkali metal hydrides, such as sodium hydride or potassium hydride: alkali metal carbonates, such as sodium carbonate or potassium carbonate: and alkali metal alkox:ides, such as sodium methoxide or potassium t-butoxide.
In the compound of formula (XX), where R3 represents a hydrngen atom, the compound may be the desired compound of formula (VI) or it may be hydrolised in Step B9 t;o give the free acid of formula (XXI).
However, where R3~ represents a nitro grou p, it is necessary that this should be reduced to an amino group and form they compound of formula (XXII); this may be the desired compound or it may likewise be hydrolised to give the compound of formula (XXI).
Where R3 in t:he compound of formula (XII) used as the starting material in this Reaction Scheme represents a vitro group, this compound may be prepared by nitration of the corresponding compound where R3 represents a hydrogen atom, e.g. as shown below:

I I
F C COOH F C COON
~ r ~~ r ~ r ~~ r c c c c ii ~ -.~ ii c c c c v it v r v it v X C X' X C X' As an alternative to Steps B8, B10 and B11, where R3 represents a vitro group, the compound of formula (XIX) [shown in the following Scheme as formula (XIXa)) may be reduced to give the amino compound;.also the compound of formula (XVIII) where R3 represents a nitro group [shown in the following Scheme as formula (XVIIIa)J m,ay be reduced to the corresponding amino compound; after which the products may be treated as shown also in Reaction Scheme B':
i Reaction Scheme' M 02 II , ~ ti N2 0 F C-C-COOR~'~ Strp 8 1 F C-C-COOR»
i ~eductio n CN C J , CN
~X~ ~~ ~, R14 X XI '~.~ ~ R1 b, Rl ~~R~S R1 ~~ l5 R
( xviii a) ( xviiib Step 8 2 F \ C-C-COOA~~
[D-!I HyJ I C H
I
X
(XIXb~
Step 8~3 [b a s e]
Step 8 4 0 [reduction]
II
F C - C -COOR» F COOR»
C
X X1 ' X
R~ N H! --4 R
(XIXa) IXXII ) In the above formulae, R1, R14, R15, R17, X
and X' are as defined above.
Those compounds of formula (XII) in which R3 represents .a hydrogen atom and R1 represents a difluoromet:hoxy group can be prepared as shown in Reaction Sciheme C, whilst those in which R3 represents ;a hydrogen atom and R1 represents a trifluoromethoxy group can be prepared as shown in Reaction Scheme D:

.. 1341 Opg _ Reaction Schenne C
F OOH F COR~6 Step C 1 ~ , esterification or ~ ,/
X t~ ami dat ion X X~
OH OH
(XXIII) (XXIV1 Step C;~ . St ep C3 Base Base Xa-CH FZ Xa-CHFZ
F OOH F COR»
Step C4 ,~ hydrolysis X
X

(XXV ) tXXVI) 1 341 009 ' ~t 7 Reaction Scheme 0:
F \ COON F \ COR~6 .Step 01 _ ~ esterificat~on or r X ~ X amidation X ~ ~X

(XXIIII (XXIY1 Step 05 Step 02 ~Xa F C~Xa F2 C \ b 2 ~X b Base X Base F \ COOH F \ COR~6 (/
X ~X X / XI
0 . 0 a (XXX) F CXa (XXVII) FZ C X
Step 06 Step 03 HF,Ag8F4 , HF, AgBF~ , HgF2 etc. HgfZ etc.
F \ C00 N F \ COR~6 Step 04 X / XI Hydrolysis X ~ X~
OCF3 (XXIX) OCF3 (XXVIIII

1341 OOg ~, In the above formulae, X and X' are as defined above, R16 z~epres~snas a Clb- C6 alkoxy group or an amino group: and X and X are the same or different and each represents a halogen atom, for example a chlorine, bromine or iodine atom, but not a fluorine atom.
In Reaction Scheme C, by replacing the compound of formula Xa-CHF2 by a compound of formula Xa-CH2F, the corresponding compounds having a monofluoromethoxy group at the 3-position can be prepared.
2,4,5-Trifluoro-3-hydroxybenzoic acid, and the corresponding compounds having other halogen atoms at the 2- and 4- positions, which may be employed as the starting materials in these Reaction Schemes, can be prepared by the decarboxylation by heating of the known compound, 3,5,6-trifluoro-4-hydroxyphthalic acid, or the corresponding compounds having other halogen atoms at the 3- and 5- positions, in an aqueous medium, e.g.
water or an ,aqueous solvent, as shown below:
COOH H
F C COON F C COOH
/ \\ / \ / \\ /
C C C C
il ~ --~ II
C C C C
\ // \ / \ // \
X C X' X C X' I
OH OH
(XXIII) The compounds ~of the invention possesg a powerful antibacterial) activity. Estimation by the agar plate dilution method showed an excellent growth inhibitory 1341 Opg effect against a wide range of pathogenic bacteria, including Gram-positive bacteria such as Staphylococcus aureus or Enterococcus species, and Gram-negative bacteria such as Escherichia coli, dysentery bacillus, ShiQella, Klebsiella pneumoniae, MYxomycetes, Serratia, Enterobacter; Salmonella or Pseudomonas aeruQinosa, including normally resistant strains thereof.
The compounds of the invention can be administered as conventional pharmaceutical formulations, depending upon the intended route of administration. For example, for oral administration, they may be formulated as powders, granules, tablets, capsules, syrups or similar orally administer,able formulations, which can be produced by mixing the active compound with carriers, excipients or dilating agents, such as glucose, sucrose, lactose, sorbitol, starch, polyvinylpyrrolidone, mannitol, c<ilcium carbonate, calcium phosphate, sodium chloride or boric acid. For parenteral administration, they may be formu:Lated as conventional injections suitable for, for example, intravenous or intramuscular injection. The dose will vary, depending upon the nature of the disorder, the route of administration, and the symptoms, age and body weight of the patient;
however, for: an adult human patient, a suitable dose for oral adminifctration would be from 100 mg to 1000 mg per day, which could be given in a single dose or in divided doses.
The invention is further illustrated by the _ following Examples, which illustrate the preparation of various of the compounds of the invention. The preparation of cel:tain of the starting materials employed in these Examples is illustrated in the Preparations. They activity of certain of~the compounds of the invention i.s illustrated by the subsequent Biological ~.ctivit:y data.

1 341 Opg 3-Difluorometh, OXY-2,4,5-trifluorobenzoic acid (XXV), X
X' Fl (ester route 1(a) Ethvl 2,4,5-trifluoro-3-hydroxybenzoate (XXIV), X
= X' F, R16 = C2H5 5 ml of concentrated sulfuric acid were added to a solution of .20.0 g (0.104 moles) of 2,4.5-trifluoro-3-hydroxyben:zoic acid [(XXIII), X = X' = F].(prepared as described in Preparation 13) in 500 ml of ethanol, and the mixture was heated under reflux for 4 hours. The ethanol was then removed by distillation under reduced pressure, an<i the .cesidue was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution o:E sodium bicarbonate and with water, in that order, after which it was dried over anhydrous sodium sulfate and then concentrated by evaporation under reduceil pressure, to give 16.9 g of ethyl 2,4,5-trifluoro-3-llydroxybenzoate as a colorless powder.
Mass Spectrum (CI)z m/e 221 (M+ + 1), 175 (M+ - OC2H5).
( "CI" means '~ chemic:al ionization" ) .
1(h) Ethyl 3-difluoromethoxy-2,4,5-trifluorobenzoate f (XXVI ) , X = X' I' . R16 C2H5 1.76 g (0.044 roles) of a 60% w/w suspension of sodium hydride in mineral oil was added in small portions, whilst stirring and ice-cooling, to a solution of 8.83 g (0.04 moles) of ethyl 2,4,5-trifluoro-3-hydroxybenzoate [(~:XIV), X = X' - F, R16 - C2H50]
[prepared as described in step (a) above] ~n 40 ml of dimethylformamide am d, after the addition was complete, the mixture was stirred, whilst ice-cooling, for an additional a0 minutes. At the end of this time, the reaction mi~i:ture was transferred into a 200 ml stainless steel autoclave, and then 100 ml of dimethylformamide containing 2x8.0 g (0.32 moles) of chlorodifluoromethane were added thereto, and the mixture was stirred under pressure at 95 - 7.00°C for 5 hours. At the end of this time, the dimethy7.formamide was removed by distillation under reduced pressure, and water was added to the residue, which was extracted with toluene. The extract was washed with water and dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography, using toluene as the eluent, to give 4.85 g of ethyl 3-difluoromethoxy-2,4,5-trifluoroben,zoate as a colorless liquid.
Mass Spectrum (CI): m/e 271 (M+ + 1), 225 (M+ - OC2H5).
1(c) 3-DifluoromethoxY-2,4,5-trifluorobenzoic acid f(XXV), X = X' F1 20 ml of a 6% w/v aqueous solution of sodium hydroxide were added to a solution of 5.79 g (0.021 moles) of ethyl 3-difluoromethoxy-2,4,5-tri-fluorobenzoate [(XXVI), X = X' - F, R16 - C2H50]
[prepared as described in step (b) above] in 40 ml of ethanol, and the mixture was left at room temperature overnight. 'The reaction mixture was then acidified by the addition of 3.5 ml of concentrated aqueous hydrochloric acid, and, after concentration by evaporation under reduced pressure, it was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, and then the solvent was removed by distillation under reduced pressure, to give 5.22 g of 3-difluorometlioxy-2,4,5-tri-fluorobenzoic acid as a colorless powder, melting at 68 - 70°C.

Mass Spectrum (CI:): m/e 243 (M+ + 1), 225 (M+ - OH), 223 (M+ - F), 192' (M+ - CF2), 175 (M+ - CF2 - OH).
Nuclear Magnetic Resonance Spectrum (CDC~,3, b ppm):
6.67 (1H, triplet. J = 72 Hz);
7.83 (1H, multiplet);
10.74 (1H, broad).

3-Difluoromethoxv-2,4,5,-trifluorobenzoic acid (XXV), X
= XI F1 amide route) 2(a) 2,4,5-T~ rifluoro-3-hydroxybenzovl amide f(XXIV), X
X. F. R16 N.H21 300 ml of thionyl chloride were added to a solution of 100.0 g (0.52 :moles) of 2,4,5-trifluoro-3-hydroxy-benzoic aci<i [(XXIII), X = XI - F) (prepared as described in Preparation 13) in 400 ml of benzene, and the mixture was heated under reflux for 3 hours. At the end of this time, the solvent and excess thionyl chloride were removed by distillation under reduced pressure, to give 2,4,5-trifluoro-3-hydroxybenzoyl chloride. '.the whole of this chloride was added dropwise to 1500 ml of 28% w/v aqueous ammonia, whilst stirring and ice-coo7.ing, <~nd the mixture was then stirred for a further 2 hours. At the end of this time, the mixture was allowed to stand at room temperature overnight, after which it was acidified by the addition of dilute aqueous hydi:ochlot:ic acid. The reaction mixture was then extracted with ethyl acetate, and the extract was washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by'distillation under reduced pressure, to give 88.2 g of 2,4,5-trifluoro-3--hydroxybenzoyl amide as a colorless 1 3.41 009 powder, melting at 153 - 155°C.
Mass Spectrum (CI): m/e 192 (M+ + 1), 175 (M+ - NH2).
2(b) 3-Dif:Luoromethoxy-2,4,5-trifluorobenzoyl amide j ( XXV I ) , X : X' F , R 16 NH21 5.00 g (0.026 moles) of 2,4,5-trifluoro-3-hydroxy-benzoyl amide [(X:KIV), R = X' = F, R16 - NH2]
[prepared as described in step (a) above] were dissolved in 130 ml 01: dimethylformamide. 4.70 g (0.034 moles) of potassium carbonate and 6.8 g (0.079 moles) of chloro-difluoromethane mare then added to the resulting solution, and the mixture was stirred in an autoclave at 100°C for 3 hours. At the end of this time, 500 ml of water were added tto the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with water, and the solvent was removed by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography, using a 1 . 1 by volume mixture of toluene and ethyl acetate as the eluent, to give 5..08 g of 3-difluoromethoxy-2,4,5-trifluorober,~zoyl amide as colorless needles, melting at 102 - 104°C.
Mass Spectrum (CI): m/e 242 (M+ + 1), 225 (M+ - NH2).
2(c) 3-Difluorome~thoxY-2,4,5-trifluorobenzoic acid f ( XXV ) , X = X' P~;1 30 ml of an aqueous solution containing 6.60 g (0.096 moles) of sodium nitrite were slowly added dropwise, whilst stirring and ice-cooling, to a suspension of 15.5.3 g (0.064 moles) of 3-difluoro-methoxy-2,4,5-trifluorobenzoyl amide [(XXVI), X = X' -F, R16 - NH2] [prepared as described in step (b) above] in 20 ml of concentrated aqueous sulfuric acid.

and the mixture was heated under reflux for 30 minutes.
At the end of this time, it was cooled to room temperature, and then 50 ml of water were added it. The reaction mi:Kture 'was then extracted with chloroform.
The extract was washed with water and dried over anhydrous sodium sulfate, and then the solvent was removed by distillation under reduced pressure, to give 15.59 g of 3-difluoromethoxy-2.4,5-trifluorobenzoic acid as a colorless powder.
This compound had the same melting point, mass spectrum anii nuclear magnetic resonance spectrum data as that obtained through the ester route in Preparation 1.

3-Difluorome~thoxy--2,4.5-trifluorobenzoic acid ((XXV), X
X' = F] (direc t method) 20 ml of dimethylformamide, followed by 4.97 g (0.026 mole) of 2"4,5-trifluoro-3-hydroxybenzoic acid [(XXIII). X = X~ .- F], were added in portions, whilst ice-cooling, to a solution of 2.18 g (0.052 mole) of sodium hydroxide im 5 ml of water. Thereafter the solution was stiri:ed for 30 minutes, whilst ice-cooling. The reaction mixture was then transferred to a 200 ml stainless steel autoclave, and 100 ml of dimethylform;amide containing 24.0 g (0.277 mole) of chlorodifluoromethane were added to it. The mixture was then stirred at between 100 and 110°C for 5 hours under pressure. A.t the end of this time, the reaction mixture was poured into water and extracted with chloroform.
The chloroform extracts were washed with water and dried over anhydrous soelium sulfate; the solvent was then removed by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel using a~ 9 . 1 by volume mixture of ethyl - - .

acetate and ethanol as the eluent, to afford 2.00 g of 3-difluoromethoxy-2,4,5-trifluorobenzoic acid as a colorless powder.
This compound had the same melting point, mass spectrum and nuclear magnetic resonance spectrum data as that obtained through the ester route in Preparation 1.

2,4.5-Trifluoro-3-trifluoromethoxybenzoic acid f(XXIX), X = X' Fl 4(a) Ethvl 3-bromodifluoromethoxY-2.4.5-trifluoro-benzoate ((7tXVII , X = X' F, Xa = Br, Ri6 =

1.0 g (0.025 moles) of a 60% w/w suspension of sodium hydride in mineral oil was added in small portions, whilst atirring and ice-cooling, to a solution of 5.0 g (0.023 moles) of ethyl 2,4,5-trifluoro-3-hydroxybenzoate [(XXiV), X = X' - F, R16 C2H50] [prepared a s described in Preparation 1(a)]
in 20 ml of dimethylformamide and, after completion of the addition, the mixture was stirred, whilst ice-cooling, for a n additional 30 minutes. After this, 130 ml of di.methy:Lformamide containing 28.0 g (0.13 moles) of d:ibromodifluoromethane were added, and the mixture was shirred at room temperature for 23 hours. At the end of this time, the reaction mixture was poured into 300 ml of water, and extracted with toluene. The extract was washed with water and dried over anhydrous sodium sulfate, and then the solvent was removed by distillation under reduced pressure. The residue was subjected to silica gel columh chromatography, using toluene as the eluent, to give 5.60 g of ethyl 3--bromodifluoromethoxy-2,4,5-trifluoro-benzoate. as a colorless liquid.
Mass Spectrum (CI;): m/e 351 (M+ + 3), 349, (M+ + 1).
4(b) Ethyl 2,4,5--trifluoro-3-trifluoromethoxybenzoate [ (XXVII I ) , ~S; = X' F. R16 C2H501 1.50 g (0.004: moles) of ethyl 3-bromodifluoro-methoxy-2,4,5-tril:luorobenzoate [(XXVII), X = X' - F, Xa = Br, R'6 = C2Ei50] [prepared as described in step (a) above] was dissolved in 10 ml of toluene, and 2.50 g (0.013 moles) of silver tetrafluoroborate were added thereto. The mixture was then heated under reflux for 8 hours in they dark, whilst stirring. At the end of this time, the reaction mixture was filtered, and the filtrate was washed with water, dried over anhydrous sodium sulfate, arid concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography, using toluene as the eluent, to give 1.12 g of ethyl 2,4,5-trifluoro-3-trifluoro-methoxybenzoate as. a colorless liquid.
Mass Spectrum (CI): m/e 289 (M+ + 1), 269 (M+ - F).
4(c) 2,4.5-'Trifluoro-3-trifluoromethoxybenzoic acid [(XXIX), X = X' F1 19.3 ml (0.0193 moles) of a 1N aqueous solution of sodium hydro:Kide were added to a solution of 5.05 g (0.0175 moles) of ethyl 2,4,5-trifluoro-3-trifluoro-methoxybenzo,3te [(XXVIII). X = X' - F, R16 -C2H50] [prep~3red as described in step (b) above) in 100 ml of ethanol, and the mixture was allowed to stand at room temperature for 2 hours. At the end of this time, 19.3 m:L of 1N aqueous hydrochloric dcid were added, and then the reaction mixture was concentrated by evaporation under reduced pressure. The residue was 1 341 O~g v then extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure, to give 3.98 g of 2,9:,5-trifluoro-3-trifluoromethoxybenzoic acid as a colorless powder.
Mass Spectrum (CI): m/e 261 (M+ + 1), 243 (M+ - OH).
Nuclear Magnetic Resonance Spectrum (CDC~,3, b ppm):
7.88 (1H, multiplet).

3-Difluoromethoxv-2.4,5-trifluoro-6-nitrobenzoic acid f(XII), R1~ -OCHF.2, R3 = N02, X = X' = F]
20 ml of concentrated aqueous nitric acid (d - 1.42) were added dropwise, whilst stirring and cooling with water, to a solution of 15.0 g (0.062 moles) of 3-difluoromethoxy-2,4,5-trifluorobenzoic acid [(XXV), X
- X' - F] (prepared as described in Preparation 1, 2 or 3) in 40 ml of concentrated aqueous sulfuric acid, and the mixture Haas stirred at 60°C for 7 hours. At the end of this time, it was allowed to stand to cool to room temperature, and then the reaction mixture was poured into ice-water, and extracted with diethyl ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate:
the solvent was then removed by evaporation under reduced pres~aure, to give 16.6 g of 3-difluoromethoxy-2,4,5-trifluoro-6-nitrobenzoic acid as a yellow powder, melting at 7'7 - 80°C.
Mass Spectrmn: m/e 287 (M+), 243 (M+ - C02).

1341 pig Ethyl 1-cyc:loprop~Yl-8-dif luoromethoxy-6, 7-dif luoro-1, 4-dihvdro-4-o:~coauinoline-3-carboxvlate f(XX), R1_=
-OCHF2, R3 _ H. 1R1~ = C2H5, X = F]
6(a) Diethyl 3-d:ifluoromethoxy-2,4,5-trifluorobenzoyl-malonate f (7CIV R1 = 3' 17 -OCHF -2,, R = H , R--C2H5~. X = X ~F l _ 15 ml ol: thionyl chloride were added to a solution of 5.22 g (0.0216 moles) of 3-difluoromethoxy-2,4,5-trifluorobenzoic acid [(XII~, R1 = -OCHF2, R3 =
H. X = X' = F] (prepared as described is Preparation l, 2 or 3) in 3.00 ml of benzene, and the mixture was heated under reflux: for :: hours. At the end of this time, benzene and excess thionyl chloride were removed by distillation under: reduced pressure, to give 3-difluorome~thoxy--2,4,5-trifluorobenzoyl chloride [(XIII), R1 - -OCHF2, R3 - H. X = X' - F].
Meanwhile, a suspension of diethyl ethoxymagnesium malonate in diethyl ether was prepared from a mixture of 2.80 g (0.0238 moles) of magnesium ethoxide and 3.81 g (0.0238 moles) of diethyl malonate in 60 ml of anhydrous diethyl ether by heating under reflux for 1 hour, whilst stirring. A solution of the 3-difluoromethoxy-2,4,5-trifluorobenzoyl chloride prepared as described above in 50 ml of anhydrous. diethyl ether was then added dropwise to the suspension, whilst stirring at room temperature, and the mixture was then stirred at room temperature for an additional 2 hours. 35 ml of 1N aqueous hydrochloric acid were added to the reaction mixture, and the mixture was vigorously stirred. The organic layer was then separated, washed with water and dried over anhydrous sodium sulfate. T'he solvent was then removed by evaporation under reduced pressure to give 7.07 g of 1 341 nA9~"~

diethyl 3-di.fluoromethoxy-2,4,5-trifluorobenzoylmalonate [ (XIV) . R1 _. _OCHF'2. R3 - H, R1~ - C2H5. X
= X' - F] as a brown liquid.
Mass Spectrum (CI): m/e 385 (M+ + 1), 339 (M+ - OC2H5).
6(b) Ethyl 3-difl.uoromethoxy-2,4,5-trifluorobenzovl-acetate f(XV)-RR1_ -OCHF2. R3 = H, R1~ _ C2H5. X = X'F7F7 The whole of t:he diethyl 3-difluoromethoxy-2,4,5-trifluorobenzoylma~lonate [(XIV), R1 = -OCHF2, R3 - H. R1~ = C2H5, ~; = X' = F] [prepared as described in step (a) above] was dissolved in 200 ml of dioxane, and then 4.52 g (0.0238 moles) of p-toluene-sulfonic acid mono~hydrate were added to the resulting solution. The mixture was then heated under reflux for 6 hours. At the end of this time, the reaction mixture was concentrated b~y evaporation under reduced pressure.
100 ml of water anal 2.52 g (0.03 moles) of sodium bicarbonate were added to the residue, and the mixture was extracted with. ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to give 5.66 g of ethyl 3-difluoromethoxy-2.4,5-trifluorobenzoylacetate as a reddish brown liquid.
Mass Spectrum (CI): m/e 313 (M+ + 1), 225 (M+ - CH2COOC2H5).
- 6(c) Ethyl 3-. CYClopropylamino-2-(3-difluoromethoxY-2,4,5-triflu~orobenzovl)acrylate f(XIX). R1 -OCHF2.L
R3 - H. Rl~. C2H5. X = X' F]
20 ml of acetic anhydride and 6 m1 of~ethyl orthoformate were added to the whole of the ethy l 3-difluoromethoxy-2,4,5-trifluorobenzoylacetate [(XV), R1 - -OCHF2,, R3 - H. R17 _ C2H5. X = X' F] prepared as described in step (b) above, and, after the mixture had been heated under reflux for 2 hours, the excess acetic anhydride and ethyl orthoformate were removed by evapo ration under reduced pressure. The residue was dissolved in 200 ml of methylene chloride, and 1.25 g 1;0.022 moles) of cyclopropylamine was added dropwise, whilst ~atirring and ice-cooling; the stirring was continued, whilst ice-cooling, for an additional 1 hour. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using a 9 . 1 by volume mixture of toluene and ethyl acetate as the eluent, to give 3.29 g of ethyl 3-cyclopt:opylamino-2-(3-difluoromethoxy-2.4.5-trifluorobenzoyl)acrylate as an amber colored liquid.
Mass Spectrum (CI): m/e 380 (M+ + 1), 225 [M+
- cPr-NH-CH=:C(COOEt) ) .
6(d) Ethyl 1-cyc7.opropyl-8-difluoromethoxy-6,7-difluoro-1,4-d_- ihYclro-4-oxoauinoline-3-carboxylate f(XX).
, R1 -OCHF2 j R3 =:- H. R1~ = C2H51 X = F l The whole of the ethyl 3-cyclopropylamino-2-(3-difluorom.ethoxy-2,4,5-trifluorobenzoyl)acrylate , j(XIX). R1 - -OCHF'2. R3 - H, R17 - C2H5. X
- X~ - F] jprepare~d as described in step (c) above] was dissolved in 150 ml of anhydrous diethyl ether, and then 0.39 g (0.0098 moles) of a b0% w/w suspension of sodium hydride in mineral oil was added in portions, whilst stirring at room temperature, to the resulting solution. After completion of the addition, the stirring was continued at room temperature for an additional 1 hour, and then the mixture was acidified by the addition of 1N' aqueous hydrochloric acid with vigorous stirring. The reaction mixture was filtered 1 341 009 ~' and washed with water and with diethyl ether, in that order, to give 1.44 g of ethyl 1-cyclopropyl-8-difluoro-methoxy-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate as colorless needles, melting at 224 - 226°C.
Mass Spectrum (CI): m/e 360 (M+ + 1).

1-Cvclourop~Y1-8-difluoromethoxv-6.7-difluoro-1,4-dihydro-4-oxoauinoline-3-carboxylic acid f(XXI), R1_ -OCHF2, R3= H. X = F
9 ml of acetic acid, 1.2 ml of concentrated sulfuric acid and 7 ml of 'water were added to 1.40 g (0.0039 moles) of ethyl 1-cyclopropyl-8-difluoromethoxy-6,7-difluoro-1,4-~dihydro-4-oxoquinoline-3-carboxylate ((XX). R1 _ -OCHF,2, R3 - H. R17 = C2H5. X =
F] (prepared as described in Preparation 6), and the mixture was heated under reflux for 1 hour. At the end of this time, it was cooled to room temperature and poured into ice-water. The precipitated crystals were collected by filtration and washed with water and with diethyl ether, in that order, to give 1.09 g of 1-cyclo-propyl-8-dif:luoromethoxy-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carbo:Kylic acid as colorless needles, melting at ~~02 - :?07°C.
Mass Spectrum (CI;): m/e 332 (M+ + 1).
Elemental analysis:
Calculated foi: C14H9F4N04:
C" 50.77%; H, 2.74%; N, 4.23%.
Found . C,. 50.53%; H, 2.79%; N. 4.06%.

1341 on9 1-CVCloprop~rl-8-difluoromethoxy-6,7-difluoro-1,4-dihydro-4-oxoyuinoliine-3-carboxylic acid boron difluoride chelate f (IX)-RR1__= -OCHF2~ R3 H, X = F1 5.63 g.of boron trifluoride~diethyl etherate were added to a fcolution of 9.50 g (0.0265 moles) of ethyl 1-cyclopropyl-8-difluoromethoxy-6,7-difluoro-1,4-dihydro-4-oxoquinoline~-3-car boxylate [(VI), R1 = -OCHF2, R3 - H, R13 = t'.2H5, ~C = F] (prepared as described in Preparation 6) in 150 ml of methyl isobutyl ketone, and the mixture was hE~ated under reflux for 6 hours. At the end of this time, the reaction mixture was cooled with ice, and the,preci.pitated crystals were collected by filtration and washed with diethyl ether and with chloroform, in that order, to give 6.15 g of 1-cyclo-propyl-8-difluoromethoxy-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid boron difluoride chelate as a colorless powder, melting at 225 - 233°C.
Mass Spectrum (CI): m/e 380 (M+ + 1).
Elemental analysis:
Calculated for C14H8BF6N04~1/2 H20:
C, 43.33%; H, 2.34%; N, 3.61%.
Found . C, 43.06%; H, 2.09%; N, 3.78%.

Ethyl 1-cyclopropYl-6,7-difluoro-8-trifluoromethoxy-1,4-dihvdro-4-oxoauino,line-3-carboxylate f(VI), R1--OCF3 , R3 H, R13.- C2H5~ X = F 7 Following a procedure similar to that'described in Preparation ti, but using 6.02 g of 2,4,5-trifluoro-3-trifluoromethoxybenzoic acid (prepared as described in 1341 O~g Preparation 4) [(:KXIX), X = X~ - F], 2.41 g of ethyl 1-cyclopropyl-6.7.-dif luoro-8-trifluoromethoxy-1, 4-dihydro-4-o~:oquinoline-3-carboxylate were obtained as colorless needles,, melting at 160 - 161°C.
Mass Spectrum (CI;>: m/e 378 (M+ + 1).

1-CVClopropyl-6.7--difluoro-8-trifluoromethoxy-1,4-dihvdro-4-ox:oauinc~line-3-carboxylic acid boron difluoride chelatE~ ((IX), R1 = -OCF3t R3 = H, X
= F
Following a procedure similar to that described in Preparation 8, but: using 2.10 g of ethyl 1-cyclopropyl-6,7-difluoro-8-tri.fluoromethoxy-1,4-dihydro-4-oxo-quinoline-3-carbo~:ylate [(VI), R1 - -OCF3, R3 - H, R13 - C2H5, X = F] (prepared as described in Preparation 9), 1.82 g of 1-cyclopropyl-6,7-difluoro-e-trifluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid boron difluoride chelate were prepared as a colorless powder, melting at 266 - 271°C.
Mass Spectrum (CI): m/e 398 (M+ + 1).
Elemental analysis:
Calculated for C14H7BF7N04~1/2 H20:
C, 41.42%; H, 1.99%: N, 3.45%.
Found . C, 41.26%; H. 1.69%: N, 3.57%.

64 ~ 3 41 0 p g 5-Amino-1-c~CY loprODYl-8-difluoromethoxy-6,7-difluoro-1,4-dihydro-4-o:KOguinoline-3-carboxylic acid t(XXII); R1 -OCHF2 . _ R=_ H, XF 7 il(a) Dietlzvl (3-difluoromethoxv-2,4,5-trifluoro-6-nitrobenzo 1 malonate [(XIV), R1 -OCHF2, R3 NO2~1~ _ (_2H5LX = X' = F ) _ -40 ml 01: thio;nyl chloride were added to a solution of 15.97 g 1;0.056 moles) of 3-difluoromethoxy-2,4,5-tri-fluoro-6-nit:roben;zoic acid [(XII), R1 = -OCHF2, R3 - N02, X = X' = F] in 50 ml of benzene, and the mixture was heated under reflux for 2 hours. At the end of this time', the benzene and the excess thionyl chloride were removed by distillation under reduced pressure to give :16.50 g of 3-difluoromethoxy-2,4-5-trifiuoro-6--nitrobenzoyl chloride [(XIII), R1 --OCHF2, R3 - N02,, X = X' - F].
Meanwhile, a suspension of diethyl ethoxymagnesium malonate in diethyl ether was prepared from a mixture of 6.82 g (0.058 moles) of magnesium ethoxide and 9.35 g (0.058 moles) of iiiethyl malonate in 150 ml of anhydrous diethyl ether by heating under reflux for 2 hours, whilst stirring.
The whole of t:he 3-difluoromethoxy-2,4,5-trifluoro-6-nitrobenzoyl chloride [(XIII), R1 - -OCHF2, R3 - NO2, X = X' - F]~ prepared as described above was dissolved in 150 ml of anhydrous diethyl ether, and this solution was added dropwise, with stirring at room temperature, to the suspension of diethyl ethoxy-magnesium malonate~. The resulting mixture was then stirred at room temperature for an additional 2 hours.
At the end of this time, 100 ml of 1N aqueous 1 34~ pOg-~
hydrochloric' acid were added to the reaction mixture, and, after the mi~cture had been vigorously stirred, the organic layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure to give 31.2 g of diethyl (3-difluoromethoxy-2,4,5-trifluoro-6-nitrobenzoyl)mal.onate [(XIV), R1 - -OCHF2, R3 N02, R17 = C2H5, ~: = X' = F] as a red liquid.
Mass Spectrum (CI): m/e 430 (M+ + 1), 384 (M+ - OEt), 270 [Hf+ - CH(COOEt)2].
11(b) Ethyl 3-difluoromethoxy-2.4,5-trifluoro-6-nitrobenzoylacetate t(XV), R1 = -OCHF R3~
2' -N02, R1~ C2H5. X - X' = Fl The whole of the diethyl (3-difluoromethoxy-2,4,5-trifluoro-6-.nitrobenzoyl)malonate [(XIV), R1 --OCHF2, R3 - N02, R17 - C2H5, X = X' - F]
obtained as described in step (a) above was dissolved in 300 ml of dioxane, and 10.6 g (0.056 moles) of p-toluenesul:Eonic acid monohydrate were added to the resulting solution. The mixture was then heated under reflux for 4 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pres~aure. 150 ml of water and 4.7 g (0.056 moles;) of sodium bicarbonate were added to the residue, which was then extracted with toluene. The extract was washed with water and dried over anhydrous sodium sulfate: the solvent was then removed by distillation under reduced pressure, to give 19.4 g of ethyl 3-difluoromethoxy-2,4,5-trifluoro-6-nitrobenzoyl-acetate as a red liquid.
Mass Spectrum (CI): m/e 358 (M+ + 1), 312 ' (M+ - OEt), x'.70 (M~ - CH2C02Et).

1341 ~~9 11(c) Ethyl 2- 3.-difluoromethoxy-2,4.5-trifluoro-6-nitrobenzoyl -3-ethoxyacrylate f(XVI), R1 -OCHFZL
R3 N02~R17 C2H5 ~ X - X ~ = F ) -38 ml o:E acetic anhydride and 11 ml of ethyl orthoformate were added to the whole of the ethyl 3-difluoromethoxy-2.4,5-trifluoro-6-nitrobenzoylacetate [(XV), R1 = 3' 17 -OCHF,2 , R = N02 , R = C2H5 ' X = X' = F] prepared as described in step (b) above' and then the mixture was heated under reflux for 3 hours:
the excess acetic anhydride and ethyl orthoformate were then removed by evaporation under reduced pressure, to give 20.6 g of ethyl 2-(3-difluoromet~hoxy-2'4.5-trifluoro-6--nitrobenzoyl)-3-ethoxyacrylate as a red liquid.
Mass Spectrum (CI;I: m/e 414 (M+ + 1), 367 (M+ - N02).
11 (d ) Ethyl 3cyccyc:lopropvlamino-2- ( 3-d if luoromethoxy-214,5-trifluoro-6--nitrobenzoyl)acrylate f (XIX), R1_ -OCHF2; R3 - Np2l R17 C2H5~ R = X~ F1 The whole of t:he ethyl 2-(3-difluoromethoxy-2'4,5-trifluoro-6-nitrot~enzoyl)-3-ethoxyacrylate [(XVI). R1 - -OCHF2. R3 - N02, R17 - C2H5. X = X' - F]
obtained as described in step (c) above was dissolved in 500 ml of methylen.e chloride, and 3.5 g (0.06 moles) of cyclopropylamine were added dropwise to the resulting solution, whilst stirring and ice-cooling. The mixture was then stirred for 1 hour, whilst ice-cooling, and then for an .additional 1 hour at room temperature, after which the solvent was removed by evaporation under reduced presaure. The resulting residue was subjected to silica gel column chromatography using a 9 . 1 by volume mixtu.ce of toluene and ethyl acetate as the eluent' to give 19.8 g of ethyl 3-cyclopropylamino-2-(3-difluoromethoxy-2,4,5-trifluoro-6-nitrobenzoyl)-f 341 ppg -~

acrylate as an yellow powder, melting at 105 - 106°C.
Mass Spectrum (CI): m/e 425 (M+ + 1), 379 (M+ - OEt).
11(e) Ethyl. 1CYClopropvl-8-difluoromethoxy-6,7-difluoro-5-vitro-:L,4-dihYdro-4-oxocuinoline-3-carboxylate ((XX), R1 = -OCHF-~. R3 N02. R1~ = C2H5t X = F
1.0 g (0.0024 moles) of ethyl 3-cyclopropylamino-2-(3-difluoromethoxy-2,4,5-trifluoro-6-nitrobenzoyl)-acrylate [(X:IX), R1 = -OCHF2, R3 = N02, R17 -C2H5, X = X' = F] [prepared as described in step (d) above] was dissolved in 10 ml of tetrahydrofuran, and 0.094 g (0.0024 moles) of a 60~ w/w suspension of sodium hydride in mineral oil was added to the resulting mixture. The mixture was then stirred at room temperature for 1 hour, after which 1N aqueous hydrochloric acid was added, and the mixture was vigorously stirred to acidify the whole mixture. The crystals which precipitated were collected by filtration and washed with water and with diethyl ether, in that order, to give 0.6 g of ethyl 1-cyclopropyl-8-difluoro-methoxy-6,7-difluoro-5-vitro-1,4-dihydro-4-oxo-quinoline-3-carboxylate as a pale yellow powder, melting at 262 - 268°C.
Mass Spectrum (CI): m/e 405 (M+ + 1), 358 (M+ - N02).
Nuclear MagnE~tic Resonance Spectrum (hexadeuterated dimethylsuli:oxide, b ppm):

1.05 (4H, mult:iplet);

1.22 (3H, trip:let):

3.91 (1H, mult:iplet);

4.18 (2H, quartet); ' 7.24 (1H, triplet, J - 72 Hz);

8.56 (1H, sing:Let).

~-34~ X09 11(f) Ethyl 5-am:ino-1-cYClopropvl-8-difluoromethoxy-6,7-difluoro-1,4-dihydro-4-oxoauinoline-3-carboxylate ( (XXI I ) . R1_ -OC13F2~ R1~ C2H5s X = F ]
3.0 g (0.0074 moles) of ethyl 1-cyclopropyl-8-difluoromethoxy-6"7-difluoro-5-nitro-1.4-dihydro-4-oxo-quinoline-3-~carboxylate [(XX), R1 - -OCHF2, R3 -N02, R17 - C:2H5, 7C = Fj [prepared as described in step (e) above] were dissolved in 800 ml of acetic acid by heating. 0.75 g of 5% w/w palladium-on-carbon was then added to the solution, and the mixture was stirred at 70 - 80°C for 3 hours under a current of hydrogen. At the end of this time, the reaction mixture was filtered, and the filtrate was concentrated by evaporation under reduced pressure. The residue was washed with diethyl ether to give 1.78 g of ethyl 5-amino-1-cyclopropyl-8-difluoromethoxy-6,7-difluoro-1,4-dihydro-4-oxoq,uinoline-3-carboxylate as a colorless powder, melting at 295 - 296°C.
Mass Spectrum (CI): m/e 375 (M+ + 1), 329 (M+ - OEt).
11(f') Ethyl 5-am.ino-1-cyclopropvl-8-difluoromethoxy-6,7-difluoro-1,4-dihYdro-4-oxo4uinoline-3-carboxylate f(XXII), R1- -OCHF2, Rl~ C2H5f X = F]
The compound of Preparation 11(f) was also synthesised 'by the following method.
33.63 g (0.079 mole) of ethyl 3-cyclopropylamino-2-(3-difluoromethoxy-2,4,5-trifluoro-6-nitrobenzoyl)-acrylate [(XIXa): X = X' - F. R1 - OCHF2, R17 -C2H5j were dissolved in 1300 ml of ethanol with heating. A estream of hydrogen was then bubbled through the solution in the presence of 8.4 g of 5~% w/w palladium-on--carbon at room temperature for 40 minutes, whilst stirring. .At the end of this time, the reaction mixture was :filtered, and the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was 'then purified by silica gel column chromatograplny using a 9 . 1 by volume mixture of toluene and ethyl acetate as the eluent, to give 25.1 g of ethyl 3-cyclopropylamino-2-(6-amino-3-difluoro-methoxy-2.4,5-trifluorobenzoyl)acrylate [(XIXb): X = X' = F, R1 = OC13F2. R17 = C2H5] as a pale yellow powder, melting at 103 - 104°C.
Mass Spectrwn (CI): m/e 395 (M+ + 1).
The whole of the ethyl 3-cyclopropylamino-Z-(6-amino-3-difluoromethoxy-2,4,5-trifluorobenzoyl)acrylate prepared as described above was dissolved in 340 ml of tetrahydrofuran, and 3.82 g (0.096 mole) of a 60% w/w dispersion o~E sodium hydride in mineral oil were added slowly to th~a resulting solution, whilst ice-cooling.
The mixture was then stirred at the same temperature for 30 minutes, and then at room temperature for a further 1 hour. At the end of this time, the reaction mixture was acidified by the addition of 96 ml of 1N aqueous hydrochloric acid, whilst stirring vigorously. The resulting pr~acipitate was collected by filtration and washed with water and with ethanol, in that order, to give 18.76 g of ethyl 5-amino-1-cyclopropyl-8-difluoro-methoxy-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate [(XXII). R1 - -OCHF2. R17 - C2H5' X = F] as a colorless powder, melting at 295 - 296°C.
~ Mass Spectrum (CI): m/e 375 (M+ + 1).
11(a) 5-Amino-1-cyclopropyl-8-difluoromethoxy-6,7-difluoro-1,4~-d_ ihydro-4-oxoguinoline-3-carboxylic acid f(XXI), R1- -OCHF2, R3 NH2, X = F] ' A suspen:aion of 3.58 g (0.0096 moles) of ethyl 5-amino-1-cyclopropyl-8-difluoromethoxy-6,7-difluoro-1,4-dihydro--4-oxoquinoline-3-carboxylate [(XXII), R1 --OCHF2, R17 - C2H,~, X = F] (prepared as described in step (f) or (f~) above], 21 ml of acetic acid, 2.8 ml. of concentrated sulfuric acid and 15 ml of water was heated under reflux, with stirring, for 1 hour, after which it was cooled by allowing it to stand. Wate:r was then added to the reaction mixture, and the insoluble materials were removed by filtration and washed with water and with diethyl ether, in that order, to give 3.0 g of 5-amino-1-cyclopropyl-8-difluoromethoxy-6"7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic' acid as a pale yellowish green powder.
melting at f84 - :?86°C.
Mass Spectrum (CI;I: m/e 347 (M+ + 1), 329 (M+ - OH), 302 (M+ - CC~2 ) .
Nuclear Magnetic Resonance Spectrum (hexadeuterated dimethyl sulfoxidE~, b ppm):
0.8 - 1.2 (4H" multiplet):
3.92 (1H, mult:iplet);
7.05 (1H, triplet, J - 73 Hz);
7.92 (2H, broad singlet);
8.62 (1H, sin<~let);
14.25 (l.H, singlet) .
Elemental an~alysifa Calculated fol: C14H10F4N204' C,, 48.57%: H, 2.91%: N. 8.09%.
Found. . C" 48.45%; H, 2.53%; N, 8.03%.

1.3 41 009 5-Amino-1-c3 cr lopropyl-8-dif luoromethoxy-6 , 7-dif luoro-1,4-dihYdro--4-oxo~~uinoline-3-carboxylic acid boron difluoride c:helat~e ((IX). R1 -OCHF2, R3 NH2t X = F
0.96 g of boron trifluoride~diethyl etherate was added to a caixtur~e of 1.17 g (0.0034 mole) of 5-amino-1-cyclopropyl-8-d:ifluoromethoxy-6,7-difluoro-1,4-dihydro-4-oxoquinolime-3-carboxylic acid [(XXI). R1 --OCHF2. R3 == NH2. X = F. Or (VI). R1 = -OCHF2.
R3 = NH2, R~'3 = H. X = F] (prepared as described in Preparati-on 11.) and 30 ml of methyl isobutyl ketone, and the mixture was heated under reflux for 6 hours. At the end of this time, the mixture was cooled with ice, and the crystals which precipitated from the reaction mixture werE~ collected by filtration and washed with diethyl ethE~r to afford 1.29 g of 5-amino-1-cyclopropyl-8-dif luorome!thoxy--6, 7-dif luoro-1, 4-dihydro-4-oxo-quinoline-3--carboo~cylic acid boron difluoride chelate as yellow crystals, taelting at not less than 300°C.
Mass Spectrum (CI;): m/e 395 (M+ + 1).
Elemental analysis:
Calculated 1'or C14H9BF6N204:
C, 4:?.68%; H, 2.30%; N. 7.11%.
Found: C. 4:?.29%: H, 2.20%; N, 7.08%.

2,4,5-Trifluoro-3--hydroxybenzoic acid ((XXIII), X = X

2700 g c>f 3,5"6-trifluoro-4-hydroxyphthalic acid and 6 liters of water were placed in an autoclave, and the ~ 341 009 mixture was heated at 140°C for 3 hours in an atmosphere of nitrogen. At t;he end of this time, the reaction mixture was cooled to room temperature and concentrated by evaporation under reduced pressure, to precipitate crystals, which were collected by filtration, washed with chloroform and dried to give 1623 g of 2.4.5-tri-fluoro-3-hydroxybe~nzoic acid [(XXIII). X = X' = F) as a colorless powder, melting at 144 - 146°C.
Mass Spectrum: m/e~ 192 (M+).
Nuclear Magnetic Resonance Spectrum (CD30D, b ppm):
4.94 (1H, broad singlet);
7.25 (1H:, mull;iplet).

(2S)-MethYlpiperazine 14(a) Ethyl NcYanomethYl-L-alanate ml of water, followed by 3.2 g (0.065 mole) of sodium cyanide, were added to 10 g (0.065 mole) of ethyl _L-alanate hydroch7loride. 5.3 g (0.065 mole) of a solution of 37% by weight of formaldehyde in water were then added d.ropwise to the mixture. During this addition, the reaction temperature increased to nearly 40°C. The resulting mixture was then stirred at room temperature for 6 hours, after which it was allowed to stand overnight at the same temperature. The reaction mixture was then extracted with methylene chloride, and the organic extract was washed with a saturated aqueous solution of sodium bicarbonate and with water, in that order. It was than dried over anhydrous sodium sulfate and concentrated by evaporation under red~iced pressure.
The residue was purified by column chromatography through silica ge:l, using a 9 . 1 by volume mixture of toluene and ethyl acetate as the eluent, to afford 5.b g of ethyl N-cyanomethyl-L-alanate as a colorless oil.
Mass Spectrum (CI): m/e 157 (M+ + 1), 130 (M+ - CN).
Nuclear Magnetic Resonance Spectrum (CDC~.3) b ppm:
1.28 (3Fi, triplet, J=6Hz);
1.33 (3H, doublet, J=6Hz);
2.15 (1H, singlet);
3.45 (1H, quartet, J=bHz);
3.60 (2E(, singlet);
4.20 (2H:, quartet, J=6Hz).
14(b) (3S)-Methyl-2-oxopiperazine A mixture of 5.0 g (0.321 mole) of ethyl N-cyano-methyl-L-alanate [prepared as described in step (a) above], 56 g of ethanol containing 4$ w/w ammonia and 1.38 g of Raney nickel was transferred to an autoclave where it was then stirred under a hydrogen pressure of 50 kg/cm2 at 90°C for 2 hours. At the end of this time, the catalyst was removed by filtration and the solvent was atripped from the filtrate by evaporation under reduced pressure. The residue was purified by column chrom~~tography through silica gel using a 1 . 20 by volume mi:KturE~ of methanol and chloroform as the eluent, to a~'forii 2.8 g of (3S)-methyl-2-oxopiperazine as colorless crystals.
Mass Spectrurn (CI): m/e 115 (M+ + 1).
Nuclear MagnE~tic Resonance Spectrum (CDC~,3) b ppm:
1.40 (3H, doublet, J=6Hz);
1.78 (1H, singlet):
2.9 - 3.E. (5H, multiplet);
7.00 (1H, broad).

14(c) (2S)-~Methylpiperazine A solution of 2.29 g (0.020 mole) of (3S)-methyl-2-oxopiperazin.e [prepared as described in step (b) above]
in 35 ml of tetrahydrofuran was added dtopwise to a suspension of 1.53 g (0.040 mole) of lithium aluminum hydride in 35 ml of tetrahydrofuran, and the mixture was heated under reflux for 5 hours. It was then allowed to cool, after which a small amount of water was added to the reaction mixture, whilst ice-cooling, to decompose any excess of the reducing agent. The reaction mixture was then filtered, and the filtrate was mixed with 10 ml of concentrated aqueous hydrochloric acid and evaporated to dryness under reduced pressure. The residue was triturated with a mixture of diethyl ether and ethanol to give 2.73 g of (2S)-methylpiperazine dihydrochloride as a colorle;as pawder, which was dissolved in 10 ml of water. The pH of the aqueous solution was adjusted to a value greater: than 10 by the addition of a 10% w/v aqueous solu~:ion of sodium hydroxide, and then the mixture was Extracted with chloroform. The chloroform extract was iiried over anhydrous sodium sulfate and the solvent was t:emoved by evaporation under reduced pressure. 1.30 g of (2S)-methylpiperazine was obtained as colorless needles by vacuum distillation of the residue. It was determined by high pressure liquid chromatography analysis [using GITC (2,3,4,6-tetra-O-acetyl-S-D-glucopyranosyl isothiocyanate) derivatives]
that the product was an S-isomer having an optical purity of 98.5%.
Mass Spectrum. (CI): m/e 101 (M+ + 1).
Nuclear Magnetic Resonance Spectrum (CDC~3) b ppm:
1.00 (3H, doublet, J=6Hz);
1.85 (2H, singlet);
2.30 - 2.45 (1H, muitiplet);

1341 pp9 2.6 ~ 3.0 (6H, multiplet).

Following a procedure similar to that described in Preparation 14, but using the starting materials listed in Table 2, the following piperazine derivatives were synthesized.
Table 2 Preparation Starting Product m.p.(°C) No. material (piperazines) 15 L-a-aminobutyric (2S)-ethyl- 231-239 acid piperazine 2HC~.
16 L-valine (2S)-isopropyl- 261-264 piperazine 2HC~
17 2-aminoisobutyric 2,2-dimethyl- 229-240 acid piperazine 2HC~
18 1~L-O--methylserine DL-2-methoxy- 199-204 methylpiperazine 2HC~.

~S~-Aminopyrrolidine dihydrochloride 19(a) Ethyl N-t-butox5rcarbonYl-L-aspartate 7.33 g (0.072 mole) of triethylamine c~ere added, whilst ice-cooling, to a solution of 14.88 g (0.066 mole) of ethyl L-aspartate hydrochloride x.34? X09 dissolved i~1 200 ml of methylene chloride. The mixture was then starred for 20 minutes, after which 14.4 g (0.066 mole;l of di-t-butyl dicarbonate were added to it in portions.. When the addition was complete, the mixture was stirred for 2 hours and then concentrated by evaporation under reduced pressure. Toluene was added to the residue, and the triethylamine hydrochloride which precipitated was removed by filtration. The filtrate was. concentrated by evaporation under reduced pressure, and the residue was purified by column chromatograF~hy through silica gel, using a 4 . 1 by volume mixture of toluene and ethyl acetate as the eluent' to afford 18.61 g of ethyl N-t-butoxycarbonyl-L-aspartate as a colorless oil.
Mass Spectrum (CI): m/e 234 (M+ + 1 - CH2=C(CH3)2)' 190 (M+ + 1 - CO;Z - CH2=C(CH3)2)' 19(6) (2S)-t-ButoxYCarbonylamino-1,4-dihydroxybutane 40 ml of tetrahydrofuran containing 10.0 g (0.035 mole) of ethyl N-t-butoxycarbonyl-L-aspartate [prepared as described in step (a) above] were added dropwise to .a solution of 3. O1 g (0.138 mole) of lithium borohydride dissolved in 100 ml of tetrahydrofuran. The dropping rata was adjusted so that the reaction temperature was maintained at 40°C. After completion of the addition" the mixture was stirred at room temperature l:or 4 hours. At the end of this time, any excess of thE~ reducing agent was decomposed by the addition of a small amount of water. The reaction mixture was then filtered, and the filtrate was concentrated by evaporation under reduced pressure, to remove the te~trahydrofuran. Sodium chloride was then added, and tree mixture was extracted with'ethyl acetate. The organic extract was dried over anhydrous sodium sulfate and concentrated by evaporation under 134 pp9 .~
reduced pressure, to afford 6.15 g of (2S)-t-butoxy-carbonylamino-1,4-dihydroxybutane as a colorless oil.
Mass Spectrum (CI): m/e 206 (M+ + 1), 150 (M+ +
1 - CH2=C(CIH3)2), 106 (M+ + 1 - C02 - CH2=C(CH3)2)' 19(c) (2S,Z~-t-Butoxycarbonylamino-1,4-di(methylsulfonvl-oxv)butane 15.12 g (0.132 mole) of methanesulfonyl chloride were added iiropwise, whilst ice-cooling, to a solution of 13.0 g (0.060 mole)_of (2S)-t-butoxycarbonylamino-1,4-dihydroy:ybutane [prepared as described in step (b) above) and 7.4.54 g (0.144 mole) of triethylamine in 250 ml of me~thylene chloride. The mixture was stirred for 3 hours, whilst ice-cooling, after which it was allowed to stand overnight at room temperature. At the end of this time, it was mixed with water and with methylene chloride. The organic layer was separated and dried over anhydrous sodium sulfate, and then the dried organic layer was concentrated by evaporation under reduced pressure, to give 20.22 g of (2S)-t-butoxy-carbonylamino-1,4-di(methylsulfonyloxy)butane as colorless crystals.
Mass Spectrum (C:I): m/e 210 (M+ - OS02CH3 - CH2=C(CH3)2)' 19(d) (3S)-;Aminanyrrolidine dihYdrochloride 6.0 g (0.059 mole) of triethylamine were added to a suspension o:E 20.22 g (0.056 mole) of (2S)-t-butoxy-carbonylamino-1,4-di(methylsulfonyloxy)butane [prepared as described in step (c) above] in 130 ml of methanol.
Ammonia gas saas passed into the mixture until it reached saturation, rind t:he mixture was then stirred at room temperature l:or 2 days. At the end of this time, it was concentrated by evaporation under reduced pressure. The 134 p~9 ..

resulting residue was dissolved in 150 ml of methylene chloride, and then 12.22 g (0.056 mole) of di-t-butyl dicarbonate were added to the resulting solution. 23 ml of triethyl~imine were then added dropwise, and the mixture was stirred at room temperature for 2 hours.
The reaction mixture was then washed with water and dried over anhydrous sodium sulfate, after which it was concentrateci by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel using a 9 . 1 by volume mixture of toluene and ethyl acetate as the eluent, to afford (3S)-t-butoxycarbonylamino-1-t-butoxycarbonylpyrrolidine as a colorlE~ss oil. The oil was mixed with 10 ml of concentrated aqueous hydrochloric acid, and the mixture was evaporated t.o dryness under reduced pressure, and triturated with ethanol to give 2.87 g of (3S)-amino-pyrrolidine dihydrochloride as a colorless powder.
Mass Spectrum (CI): m/e 87 (M+ + 1), 70 (M+ - NH2).

3-Ami.no-4-(2.2,2-trifluoroethoxY)pYrrolidine dihYdrochloride 20(a) 1-t-ElutoxycarbonYl-3-(2,2,2-trifluoroethoxY)-4-methYlsulfonYloxYpYrrolidine 1.08 g (0.027 mole) of a 60% w/w dispersion of sodium hydride in mineral oil was added, whilst cooling with water, to 15 ml of 2,2,2-trifluoroethanol, and the mixture was stirred for 20 minutes. At the end of this time, 5.0 g (0.027 mole) of 1-t-butoxycarbonyl-3,4-epoxypyrrolidine were added to the mixture, which was then heated under reflux for 3 hours. The reaction mixture was then mixed with a saturated aqueous solution of sodium chloride and extracted with ethyl acetate.

1 341 009 ' The organic extract was dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The concentrate was dissolved in 50 ml of pyridine, anal 3.23 g (0.028 mole) of methanesulfonyl chloride were added, whilst ice-cooling, to the resulting solution. The mixture was then stirred at room temperature for 5 hours and then allowed to stand overnight at room temperature. After it had been diluted with 300 ml of water, the reaction mixture was extracted with toluene. The organic extract was dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel using a 9 . 1 by volume mixture of toluene and ethyl acetate as the eluent, to afford 7.07 g of 1-t-butoxy-carbonyl-3-(2,2,2-trifluoroethoxy)-4-methylsulfonyloxy-pyrrolidine.
20(b) 3-Ami;no-1-t-butoxycarbonYl-4-(2,2,2-trifluoro-ethoxy)pyrrolidine A mixture of 3.95 g (0.011 mole) of 1-t-butoxy-carbonyl-3-(;2,2,2-trifluoroethoxy)-4-methylsulfonyloxy-pyrrolidine [prepared as described in step (a) above]
and 100 ml o~E methanol containing 20% w/v ammonia was transferred ~~o an autoclave and then stirred at 140°C
for 10 hours. At the end of this time, the solvent was removed by d:istil.lation under reduced pressure, and the residue was iaixed with a saturated aqueous solution of sodium carbonate and extracted with ethyl acetate. The - organic extr<ict was dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure.
The residue was purified by column chromatography through sili<:a gel using a 1 . 9 by volume mixture of ethanol and ethyl acetate as the eluent, fo give 1.61 g of 3-amino-1--t-butoxycarbonyl-4-(2,2,2-trifluoroethoxy)-pyrrolidine His a colorless oil.

Mass Spectrum (CI): m/e 285 {M+ + 1), 229 (M+ +
1 - CH2=C(CH3)2)' 20(c) 3-Amino-4-(2,2,2-trifluoroethoxy)pyrrolidine dihydrochloride A mixture of 1.61 g (0.006 mole) of 3-amino-1-t-butoxycarbon.yl-4-(2,2,2-trifluoroethoxy)pyrrolidine [prepared as described in step {b) above], 30 ml of ethanol. 2 ml of concentrated aqueous hydrochloric acid and 4 ml of water was allowed to stand overnight at room temperature after which it was evaporated to dryness under reduced pressure, to afford 1.60 g of 3-amino-4-(2,2,2-trifluoroethoxy)pyrrolidine dihydrochloride as colorless crystals.
Mass Spectrum (CI): m/e 185 {M+ + 1).

3-Amino-4-methoxymethylpyrrolidine dihydrochloride 21(a) i-Benzyl-3-ethoxycarbonyl-4-hydroxyimino-pyrrolidine A solution of 24.7 g (0.1 mole) of 1-benzyl-3-ethoxycarbon~,rl-4--pyrrolidone in 135 ml of ethanol was added dropwi;ae at: room temperature to a solution of 34.7 g {0.5 ~aole) of hydroxylamine hydrochloride dissolved in 135 ml of water, and then 28.1 g (0.265 mole) of sodium carbonate were added to the mixture. Thc~ mixture was then stirred at room temperature i'or E>.5 hours, after which it was extracted with 300 ml c~f chloroform. The chloroform extract was washed with ~aatei: and dried over anhydrous sodium sulfate. It was then concentrated by evaporation under reduced pres~~ure. The residue was purified by column 1341 Opg chromatograF~hy through silica gel using a 2 . 1 by volume mixture of toluene and ethyl acetate as the eluent, to afford 15.8 g of 1-benzyl-3-ethoxycarbonyl-4-hydroxyiminopyrrolidine as a brown oil.
Mass Spectrum (CI): m/e 263 (M+ + 1).
Infrared Absorption Spectrum (capillary) vmax cm 1.
3300, 1740.
21(b) 3-Amino-1-benzyl-4-hydroxymethYlpyrrolidine A solution of 5.24 g (0.02 mole) of 1-benzyl-3-ethoxycarbonyl-4-hydroxyiminopyrrolidine [prepared as described in step (a) above] in 10 ml of toluene was added dropwi~se to 28 ml of a 3.4 M solution of sodium bis(2-methox;~ethaxy)aluminum hydride in toluene over a period of 1 l:~our,. The mixture was stirred at room temperature :Eor 1.5 hours and was then heated under reflux for 2 hours. At the end of this time, the reaction mix~:ure was allowed to cool to room temperature, after which ice and water were added to it to form a precipitate, which was removed by filtration.
The filtrate was concentrated by evaporation under reduced presfaure, and the residue was purified by column chromatography through silica gel using methanol as the eluent, to ai:ford 2.16 g of 3-amino-1-benzyl-4-hydroxy-methylpyrroli.dine as a brown oil.
Mass Spectrum (CI:): m/e 207 (M+ + 1).
Infrared Absorption Spectrum (capillary) vmax cm 1.
3150 - 39:00.

21(c) 1-Ben,zyl-3-(N-t-butoxycarbonyl)amino-4-hvdroxy-methylpyrrolidine 6.21 g (0.0285 mole) of di-t-butyl dicarbonate were added in portions at room temperature to a solution of 5.87 g (0.0285 mole) of 3-amino-1-benzyl-4-hydroxy-methylpyrrolidine [prepared as described in step (b) above] in 100 ml of methylene chloride. The mixture was stirred at room temperature for 1 day and then the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel using ethyl acetate as the eluent, to afford 6.32 g of 1-benzyl-3-(N-t-butoxy-carbonyl)ami:no-4-hydroxymethylpyrrolidine as a pale brown oil.
Infrared Absorption Spectrum (capillary) vmax cm 1.
3350, 1680 - 1720.
21(d) 3-(N-~_-Butoxycarbonvl)amino-4-hydroxymethYl-pyrrolidine A mixturE~ of a solution of 6.32 g (0.0207 mole) of 1-benzyl-3-(rJ-t-butoxycarbonyl)amino-4-hydroxymethyl-pyrrolidine :prepared as described in step (c) above]
dissolved in 100 ml of ethanol and 2.0 g of 20% w/w palladium-on--carbon was transferred to a stainless steel autoclave and stirred at room temperature under a hydrogen preEOSUre of 100 kg/cm2 for 27 hours. At the end of this time, the catalyst was removed by filtration, amd the filtrate was concentrated by evaporation under reduced pressure, to afford 3.99 g of 3-(N-t-butoxycarbonyl)amino-4-hydroxymethylpyrrolidine as a colorless crystalline oil.
a Mass Spectrum (CI): m/e 217 (M+ + 1).

1341 ~a9 Infrared.Absorption Spectrum (KBr) vmax cm 1.
3350, 3270, 1680 - 1690.
21(e) i-t-H.utoxYcarbonYl-3-(N-t-butoxycarbonYl)amino-4-hydroxYmethYlpyrrolidine 3.12 g of di-t-butyl dicarbonate were added in portions at room temperature to a solution of 3.08 g (0.0143 mole) of 3-(N-t-butoxycarbonyl)amino-4-hydroxy-methylpyrrolidine [prepared as described in step (d) above] in 50 ml of methylene chloride, and the mixture was stirred at room temperature for one_day. At the end of this time, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography through silica gel using a 1 . 1 by volume mixture of toluene and ethyl acetate as the eluent, to afford 3.99 g of 1-t-butoxycarbonyl-3-(N-t-butoxycarbonyl)amino-4-hydroxymethylpyrrolidine as colorless crystals.
Mass Spectrum (CI): m/e 317 (M+ + 1).
21(f) 1-t-Butoxycarbonyl-3-(N-t-butoxycarbonyl)amino-4-methoxYmetlzYlpyrrolidine 0.3 ml oi_' boron trifluoride~diethyl etherate was added dropwi:~e to a solution of 3.86 g (0.0122 mole) of 1-t-butoxyca~:bonyl-3-(N-t-butoxycarbonyl)amino-4-hydroxy-methylpyrrol:idine [prepared as described in step (e) above] in 190 ml of diethyl ether cooled with ice, and then an ethe~:eal solution containing 0.126 mole of diazomethane was added to the mixture over a period of 1.5 hours. 7~he mixture was stirred at the same temperature l:or 0.5 hour, after which it was allowed to stand overnight at room temperature. It c~as then mixed with a saturated aqueous solution of sodium chloride and the ethereal layer was separated. The ethereal layer was dried, and then the solvent was distilled off under reduced pressure. The residue was purified by column chromatography through silica gel using a 2 . 1 by volume mixture of toluene and ethyl acetate as the eluent, to afford 0.47 g of 1-t-butoxycarbonyl-3-(N-t-butoxycarbonyl)amino-4-methoxymethylpyrrolidine as a colorless oil.
Mass Spectrw;~a (Ca): m/e 331 (M+ + 1).
Infrared Abs~~rption Spectrum (capillary) vmax cm'1.
3330, 16'70 - 1730.
21(a) 3-Amino-4-methoxymethylpyrrolidine dihydrochloride 7 ml of GN aqueous hydrochloric acid were added to a solution of c).58 g (0.0021 mole) of 1-t-butoxycarbonyl-3-(N-t-butox7icarbonyl)amino-4-methoxymethylpyrrolidine [prepared as described in step (f) above] in 30 ml of ethanol. ThE~ mixture was then heated under reflux for 2 hours, after which it was evaporated to dryness under reduced presf~ure to give 0.43 g of 3-amino-4-methoxy-methylpyrrol~.dine dihydrochloride as a brown oil.
Mass Spectrum (CI): m/e 131 (M+ + 1).

2-Fl.uoromethylpiperazine dihydrochloride 22(a) N-Benz;yl-N-(3-fluoro-2-hydroxypropyl)ethanolamine A solution of 22.20 g (0.3 mole) of epifluorohydrin and 67.95 g (0.45 mole) of N-benzylethanolamine dissolved in 200 ml of ethanol was heated~under reflux for 5 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, arid the residue was purified by column chromatography through silica gel using ethyl acetate as the eluent, to give 64.93 g of N-benzyl-N-(3-fluoro-2-hydroxypropyl)ethanolamine as a colorless oil.
Mass Spectrum (CI): m/e 228 (M+ + 1).
22(b) N-(3-Fluoro-2-methylsulfonyloxypropyl)-N-(2-methylsulfonyloxyethyl)benzylamine 7.27 g (0.072 mole) of triethylamine were added to a solution of 6.75 g (0.03 mole) of N-benzyl-N-(3-fluoro-2-hydroxypropyl)ethanolamine [prepared as described in step (a) above] in 200 ml of ethyl acetate. Whilst stirring and ice-cooling the mixture, 8.24 g (0.072 mole) of methanesulfonyl chloride were added to it. After the resulting mixture had been stirred for 3 hours at the same temperature, an aqueous solution of sodium bicarbonate was added to it. The organic layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, to give 12.49 g of N-(3-fluoro-2--methylsulfonyloxypropyl)-N-(2-methyl-sulfonyloxyethyl)benzylamine as a pale yellow oil.
Mass Spectrunn (CI): m/e 384 (M+ + 1).
22(c) 1,4-DibenzYl-2-fluoromethylpiperazine 4.82 g (0.045 mole) of benzylamine and 9.09 g (0.09 mole) of tr:iethylamine were added to a solution of N-(3-fluoro-:Z-met:hylsulfonyloxypropyl)-N-(2-methyi-sulfonyloxye~thyl)benzylamine [prepared as described in step (b) abo~re] dissolved in 200 ml of ethanol. The mixture was heated under reflux for 2 houts and then concentrated by evaporation under reduced pressure.
100 ml of ethanol and 40 ml of a 2N aqueous solution of 1 34_1 Da9 sodium hydroxide were added to the residue, and the mixture was concentrated by evaporation under reduced pressure. Z'he residue was mixed with ethyl acetate, and insoluble materials were removed by filtration. The filtrate was freed from the solvent by evaporation under reduced pressure, and the residue was purified by column chromatograF~hy through silica gel using a 9 . 1 by volume mixture of toluene and ethyl acetate as the eluent, to afford 3.60 g of 1,4-dibenzyl-2-fluoromethyl-piperazine as a yellow oil.
Mass Spectrum (CI): 299 (M+ + 1).
22(d) 2-Fluoromethyluiperazine dihydrochloride A mixture of a solution of 23.85 g (0.08 mole) of 1,4-dibenzyl-2-fluoromethylpiperazine [prepared as described in step (c) above] in 500 ml of methanol and 33 ml of concentrated aqueous hydrochloric acid was stirred vigorously at room temperature for 1 hour in an atmosphere of hydrogen and in the presence of 1.0 g of 20% w/w palladium-on-carbon. At the end of this time, the catalyst was removed by filtration and washed with water. The filtrate and washings were concentrated by evaporation under reduced pressure, and the residue was dissolved in 200 ml of water. The resulting aqueous solution was washed vigorously with ethyl acetate and separated. The aqueous layer was concentrated by evaporation under reduced pressure, and the residue was washed with ethanol to afford 13.76 g of 2-fluoromethyl-piperazine dihydrochloride as a colorless powder, melting at 205 - 218°C.
Mass Spectrum (CI): m/e 119 (M+ + 1).

~34~~49 Elemental analysis:
Calculated for C5H13C~,2FN2:
C, 31.43%; H, 6.86%; N, 14.66%.
Found: C, 31.42%; H, 6.81%; N, 14.71%.

2S'1-Meth~rlhomopiperazine dihydrochloride 23(a) Ethyl N-cyanoethyl-L-alanate A solution of 15.3 g (0.131 mole) of ethyl L-alanate, 7.0 g (0.132 mole) of acrylonitrile and 1.0 g (0.018 mole) of sodium methoxide dissolved in 150 ml of ethanol was heated under reflux for 7 hours. After it had been allowed to cool, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue 'was purified by column chromatography through silica gel using a 4 . 1 by volume mixture of toluene and ethyl acetate as the eluent, to afford 12.5 g of ethyl N-cyanoethyl-L-alanate as a colorless oil.
Mass Spectrum (CI): m/e 171 (M+ + 1).
23(b) (3S)-Methyl-2-oxohomopiperazine A mixture of 9.8 g (0.057 mole) of ethyl N-cyano-ethyl-L-alanate prepared as described in step (a) above], 70 g of ethanol containing 4% w/w ammonia and 1.79 g of Raney nickel was transferred to an autoclave and then stirred under a hydrogen pressure of 60 kg/cm2 at 90°C for 3 hours. After the mixture had been allowed to cool, the catalyst was removed by filtration and the filtrate was concentrated by evaporation 'under reduced pressure. The residue was mixed with 2'00 m:l of xylene and 1.4 g of dibutyltin s$
oxide, and the mixture was heated under reflux for 10 hours. A fraction containing ethanol, formed during the reaction, was eliminated from the reaction system.
Subsequently, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel using a 9 . 1 by volume mixture of chloroform and methanol as the eluent, to afford 5.3 g of (3S)-methyl-2-oxohomopiperazine as pale brown crystals.
Mass Spectrum (CI): m/e 129 (M+ + 1).
23(c) (2S)-MethYlhomopiperazine dihydrochloride A mixture of 4.92 g (0.038 mole) of (3S)-methyl-2-oxohomopiperazine [prepared as described in step (b) above] in 60 ml of tetrahydrofuran was added dropwise, whilst ice-cooling, to a suspension of 2.91 g (0.077 mole) of lithium aluminum hydride in 60 ml of tetrahydrofuran, and the mixture was heated under reflux for 5 hours. After the reaction mixture had been allowed to cool, a small amount of water was added to it, whilst ice-cooling, to decompose any excess of the reducing agent. The reaction mixture was then filtered.
and 20 ml of concentrated aqueous hydrochloric acid were added to the filtrate, which was then evaporated to dryness under reduced pressure. The residue was triturated with ethanol, to give 5.93 g of (2S)-methyl-homopiperazine d:ihydrochloride as colorless crystals, melting at 211-220°C.
Mass Spectrum (C:L ) : m/e 115 (M+ + 1) .

13.41 pp9 2,6-His(fluoromethyl)piperazine dihydrochloride 24(a) N,N-B:is(3-fluoro-2-hydroxypropyl)ben2ylamine A solution of 27.28 g (0.359 mole) of epifluorohydrin and 19.20 g (0.1795 mole) of benzylamine dissolved in 200 ml of ethanol was heated under reflux for 4 hours. The reaction mixture was then concentrated by evaporation under reduced pressure, to give 46.6 g of N,N-bis ( 3-f luoro--2-hydroxypropyl ) benzylamine as a colorless oi:l.
Mass Spectruia (CI): m/e 260 (M+ + 1).
24(b) 1,4-D:ibenzyl-2,6-bis(fluoromethyl)piperazine 28.89 g x;0.286 mole) of triethylamine were added to a solution o1. 33.67 g (0.13 mole) of N,N-bis(3-fluoro-2-hydroxypropyl)benzylamine [prepared as described in step (a) abo're] in 300 ml of tetrahydrofuran. 32.76 g (0.286 mole) of methanesulfonyl chloride were then added dropwise to l:he mixture, whilst ice-cooling. After the.
mixture had been stirred at room temperature for 6 hours. 39.40 g (0.39 mole) of triethylamine, 20.87 g (0.195 mole) of benzylamine and 300 ml of ethanol were added to it, and it was then heated under reflux for 3 hours. At the end of this time, the reaction mixture was concentr<~ted by evaporation under reduced pressure, and 300 ml 01. water containing 30 g of sodium hydroxide were added to the residue. The aqueous mixture thus obtained was extracted with ethyl acetate and the organic extracts were washed with water, dried over anhydous sodium E~ulfate and concentrated by evaporation under reduce<f pressure. The residue was purified by column chromatogi:aphy through silica gel using a 20 . 1 1 341 Qpg by volume mi:~cture of toluene and ethyl acetate as the eluent, to a1'ford 1'4-dibenzyl-2,6-bis(fluoromethyl)-piperazine, :including 6.29 g of isomer A and 6.60 g of isomer B, as colorless crystals.
Rf value of isomer A: 0.7 Rf value of isomer B: 0.5 (Thin layer plate: silica gel F254' Merck; Developing solvent: a 9 . 1 by volume mixture of toluene and ethyl acetate) Mass Spectrum (CI:) of both isomers A and B: m/e 331 (M+ + 1).
24(c) 2,6-Bi.s(fluoromethYl) iperazine dihYdrochloride A mixtures of a suspension of 5.03 g (0.015 mole) of 1,4-dibenzyl-~2,6-~bis(fluoromethyl)piperazine isomer B
[prepared as described in step (b) above] in 130 ml of methanol and 6 ml of concentrated aqueous hydrochloric acid was stinted vigorously under a stream of hydrogen at room temperature f or 1 hour in the presence of 0.6 g of 20% w/w palladium-on-carbon. At the end of this time, the catalyst was removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure. Tlue residue was mixed with 50 ml of water, and the resulting insoluble materials were removed by filtration. The filtrate was concentrated by evaporation under reduced pressure, and the residue was washed with ethanol, to afford 3.10 g of 2,6-bis(fluoro-methyl)pipera.zine (isomer B) dihydrochloride as a colorless po~~der, melting at 207 - 225°C.

Mass Spectrum (CI): m/e 151 (M+ + 1).

13_41 p~9 Elemental analysis:
Calculated for C6H14C~2F2N2.
C, 32.30%; H, 6.32%; N, 12.56%.
Found: C, 32.38%; H, 6'26%; N, 12.60%.
The above procedure was repeated but using 1,4-dibenzyl-2,6-bis(fluoromethyl)piperazine (isomer A) to afford 2.6-bis(f'luoromethyl)piperazine (isomer A) dihydrochloride as a colorless powder.
Mass Spectrum (Cx): m/e 151 (M+ + 1).
Elemental analysis:
Calculated far C6H14C~.2F2N2~1/2H20:
C, 31..04%; H, 6.51%; N, 12.07%.
Found: C, 30..66%; H. 6.22%; N, 11.78%.

1-CyclopropYl-8-difluoromethoxy-6-fluoro-7-(3-methYl-piperazinyl)~-1,4--dihydro-4-oxo4uinoline-3-carboxylic acid 1.63 g (0.016 moles) of 2-methylpiperazine was added to a solution of 2.58 g (0.0068 mole) of 1-cyclopropyl-8-difluorome~Choxy-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-~~arbaxylic acid boron difluoride chelate (prepared as described in Preparation 8) in 20 ml of dimethyl sul~.oxide, and the mixture was allowed to stand at room temperature overnight. The reaction mixture was then poured :into 100 ml of water, and the crystals which precipitated were collected by filtration and washed with water. The crystals were then dissolved in 500 ml of 80% v/v a<~ueous methanol containing 15 ml of triethylaminn, and the solution was heated under reflux for 3 hours. At the end of this time, the solvent was removed by evaporation under reduced pressure, and the residue was iaashed with ethanol, to give 2.30 g of a ~ _3 ,~ ' p p 9 pale yellow powder. The whole of this powder was dissolved in 50 'ml of water, insoluble materials were removed by filtration, and the filtrate was adjusted to a pH value of 7.5 by the addition of a 1N aqueous solution of sodium hydroxide. The crystals which precipitated were collected by filtration and washed with water and with ethanol, in that order, to give 1.74 g of the title compound as fine pale yellow needles, melting at 223 - 225°C.
Mass Spectrum (CI): m/e 412 (M+ + 1).
Elemental analysis:
Calculated for C19H20F3N304~H20:
C, 53.14%: H, 5.17%; N, 9.79%.
Found: C, 53.44%: H, 4.93%; N; 9.77%.

1-CYClopropYl-8-difluoromethoxY-6-fluoro-7-(3-methyl-piperazinYl)-1,4-dihydro-4-oxocruinoline-3-carboxylic acid hydrochloride 240 ml (0.0024 moles) of 1N aqueous hydrochloric acid were added to a suspension of 1.00 g (0.0024 moles) of 1-cyclopropyl~-8-difluoromethoxy-6-fluoro-7-(3-methyl-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (prepared as described in Example 1) in 50 ml of methanol to obtain a transparent solution. This was concentrated by evaporation under reduced pressure, and the residue 'was washed with ethanol, to give 0.97 g of the title compound (hydrochloride) as a colorless powder, melting at 277 - 287°C (with decomposition).

t34~oo Elemental analysis:
Calculated for C19H21CfF3N304:
C, 50.95%; H, 4.73%; N, 9.38%.
Found: C, 50.84%; H, 4.44%; N, 9.29%.

1-Cyclopropyl-8-difluoromethoxy-6-fluoro-7-(3-methyl-pi erazinyl)-1,4-dihYdro-4-oxoyuinoline-3-carboxylic acid methanesulfonic acid salt 0.093 g (0.00097 moles) of methanesulfonic acid was added to a suspension of 0.40 g of 1-cyclopropyl-8-difluoromethoxy-6-fluoro-7-(3-methylpiperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (prepared as described in Example 1) in 50 ml of methanol to obtain a transparent solution. This was concentrated by evaporation under reduced pressure, and the residue was washed with ethanol, to give 0.47 g of the title compound (methanesulfonic acid salt) as a colorless powder, melting at 289 - 292°C (with decomposition).
Elemental analysis:
Calculated for C20H24F3N307S~1/2 H20:
C, 46.51%; H, 4.88%: N, 8.14%.
Found: C. 46.44%; H, 4.65%; N, 7.97%.

Following a procedure similar to that described in Example 1, 2 or :3, the following compounds were produced.

~3.4~ p~

_ Table 3 Ex Cpd. hydrate, salt etc m.p. (°C) No. No.
4 34 hydrate 220 221 -34 hydrochloride, sesquihydrate 218 224 =

6 34 methanesulfonate 282 284 -(decomp.) 7 5 hydrochloride, sesquihydrate 247 251 -8 43 hydrate 187 188 -cis 9 39 hydrochloride 249 253 -3 hydrate 240 241 -cis 11 3 hydrochloride, hydrate >300 cis (gradual decomposition from 295) 12 3 methanesulfonate >300 cis 13 32 hydrochloride, dihydrate 213 217 -14 45 sesquihydrate 167 170 -1 hydrate 265 268 -(decomp.) 16 179 hydrate 251 253 -(decomp.) 17 148 hydrate 232 237 --19 188 sesquihydrate 241 245 -cis (decomp.) -cis 21 147 hydrate 249 251 -22 72 hydrochloride, sesquihydrate 230 235 ; -23 59 hydrochloride, hemihydrate 252 255 -Table 3 (cont) Ex Cpd. hydrate, salt etc m.p. (°C) No. No.
24 73 hydrochloride 228 - 235 (decomp.) 25 46 hydrate 269 - 271 (decomp.) 26 48 hydrate 160 - 163 27 2 hydrochloride 283 - 289 (3-carbon (decomp.) atom of piperazinyl is in the R configuration 28 2 hydrochloride 283 - 286 (3-carbon (decomp.) atom of piperazinyl is in the S configuration 29 56 hydrochloride, sesquihydrate 270 - 275 (decomp.) 5-Amino-1-cyclopropyl-8-difluoromethoxy-6-fluoro-7-(3-methylpipera2_inyl)-1.4-dihydro-4-oxoauinoline-3-carboxYlic acid 1.30 g (0.013 moles) of 2-methylpiperazine was added to a solution of 0.90 g (0.0026 moles) of 5-amino-1-cyclopropyl-8-difluoromethoxy-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (prepared as described in Preparation 11) in 8 ml of pyridine, and the mixture was stirred at 105 - 110°C for 2 hours. At the end of this time, the solvent was removed by distillation under reduced pressure. Water was added to the residue, and i~~tno~

the resulting mixture was neutralized (to about pH 7) by the addition of acetic acid; the mixture was then extracted with chloroform. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated by evaporation under reduced pressure. The resulting residue was washed with ethanol to give 0.72 g of 5-amino-l.-cyclopropyl-8-difluoromethoxy-6-fluoro-7-(3-methylpiperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid as a yellow powder, melting at 283 - 286°C.
Elemental analysis:
Calculated for C19H21F3N404.
C, 53.52%; H, 4.96%; N, 13.14%.
Found: C, 53.35%; H, 4.93%; N, 13.00%.

Following a procedure similar to that described in Example 30, the following compounds were obtained.
Table 4 Ex Cpd. hydrate, salt etc m.p. (°C) No. No.
31 107 hemihydrate 242 - 245 32 74 hemihydrate 282 - 283 33 78 hemihydrate >300 34 76 ~3ihydrate 297 - 300 cis Cis ' 36 76 ;hydrochloride >300 cis Table 4 (cont) Ex Cpd. hydrate, salt etc m.p. (°C) No. No.
37 75 hydrochloride, hemihydrate 296 - 298 (decomp.) 38 75 hemihydrate 278 - 281 (3-carbon atom of piperazinyl is in the R configuration 39 75 sesquihydrate 278 - 281 (3-carbon atom of piperazinyl is in the S configuration (decomp.) 41 93 hydrate 264 - 266 (decomp.) (decomp.) (decomp.) 44 129 dihydrate 270 - 275 (3-carbon (decomp.) atom of piperazinyl is in the S configuration 45 109 hydrochloride, hemihydrate 257 - 259 (decomp.) (decomp.) 48 134 hydrochloride 255 - 259 (decomp.) 134 p~9 Table 4 (coast) Ex Cpd. hydrate, salt etc m.p_. (°C) No. No.
49 144 Ihemihydrate 252 - 256 (3-carlbon atom of diazepinyl is in 'the S conf iguration (3-carlbon atom of piperazinyl - .

is in vthe S conf iguration (decomp.) (decomp.) (3-carbon atom of piperazinyl is in the :~ conf iguration (decomp.) (decomp.) (decomp.) (decomp.) (decomp.) (decomp.) (decomp.) 1.341 009 Magnesium [5-amino-1-cyclopro yl-8-difluoromethoxy-6-fluoro-7-(3-methylpiperazinyl)-1,4-dihydro-4-oxoauinoline-3-carboxYlat~
23.0 ml (0.0023 mole) of a O.1N aqueous solution of sodium hydroxide were added to 1.00 g (0.00234 mole) of 5-amino-1-cyclopropyl-8-difluoromethoxy-6-fluoro-7-(3-methylpiperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (prepared as described in Example 30), and the resulting insoluble material was removed by filtration. 0.11 g (0.00115 mole) of anhydrous magnesium chloride was added to the filtrate, and the mixture was stirred at room temperature for 90 minutes.
At the end of this time, the resulting precipitate was collected by filtration and washed with water, to give 0.91 g of magnesium [5-amino-1-cyclopropyl-8-difluoro-methoxy-6-fluoro-7-(3-methylpiperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate] as a yellow powder, melting at 291 - 293°C (with decomposition).
Elemental analysis:
Calculated for C38H40F5N808Mg~2H20:
C, 50.09%; H, 4.86%: N. 12.29%.
Found: C, 50.13%; H, 4.75%; N, 12.19%.
BIOLOGICAL ACTIVITY
The antibacterial activities of a number of compounds of the invention were investigated against a wide variety' of bacteria, both Gram-positive and Gram-negative, and the results are shown in the following Tables 5 and 6 in terms of their minimal inhibitory concentrations (ug/ml).
By way cf comparison, results are also given for the 134~~~9 known compound. Norfloxacin, which, for brevity, is identified i.n the Table as "Compound A". Each compound of the invention is identified by the number of one of the foregoing Examples which illustrates its prepartion.
Table 5 Microorganism Compound of Ex. No:

StanhYlococc:us aureus 209f 0.05 <0.01 <0.01 <0.01 <0.01 0.2 56 0.05 <0.01 <0.01 <0.01 <0.01 0.4 535 0.2 <0.01 0.02 0.02 <0.01 6.2 Enterococcu~~
faecalis 681. 0.2 0.05 0.05 0.05 0.05 3.1 Escherichia coli NIHJ <0.01 <0.01 0.02 <0.01 <0.01 0.2 609 0.4 0.4 0.2 0.2 0.05 3.1 Salmonella enteritidis <0.01 <0.01 <0.01 <0.01 <0.01 0.1 Klebsiella pneumoniae 806 0.05 <0.01 0.05 0.02 0.02 0.4 846 0.02 <0.01 0.02 <0.0~. <0.01 0.4 1341 OOg Table 5 (cont) Microorganism Compound of Ex. No.

Enterobacte~r cloacae 963 0.1 0.02 0.1 0.05 0.05 0.4 Serratia marcescens 1189 0.4 0.1 0.4 0.2 0.2 0.2 Proteus wluaris 1420 .<0.01 <0.01 <0.01 <0.01 <0.01 0.02 Moraanella moraanii 1510 0.1 0.02 0.2 0.1 0.2 0.05 Pseudomonas aeruQinosa 1001 0.4 0.4 0.4 0.4 0.2 0.8

Claims (2)

1. A compound of the formula wherein R1 is a fluorinated methoxy group, X is a halogen atom and R3a is hydrogen atom, a nitro group or an amino group.

2. A compound as claimed in claim 1, wherein R1 is difluoromethoxy group.