FI94750B - Process for the preparation of intermediates useful in the manufacture of antibacterial carboxylic acid derivatives - Google Patents

Description

94750

Process for the preparation of intermediates useful in the preparation of antibacterial carboxylic acid derivatives (Separated from Application No. 903696) U.S. Patent 4,341,784 discloses certain substituted 7- (3-amino-1-pyrrolidinyl) -1-ethyl-6-fluoro-1,4-dihydro- 4-Oxo-1,8-naphthyridine-3-carboxylic acids of general formula

O

F CO2H

Rxxx v ί. ·.

NHR

The compounds have been shown to have antibacterial activity.

The Journal of Medicinal Chemistry, 22, 1358 (1980) deals with certain substituted quinoline-3-carboxylic acids having the structural formula 0

Fs <i? VVC0! "

rXXJ

c2h5 wherein -N2 may be pyrrolidinyl. See also U.S. Patent 4,146,719. The compounds have been shown to have antibacterial activity.

»· ·

Certain 7-heterocyclic substituted 1,8-naphthyridines are disclosed in Eur.J.Med.Chem. - Chemica Thera-peutica, 29, 27 (1977). U.S. Patents 3,753,993 and 3,907,808 disclose certain 7-pyridylquinolones.

2 94750

European patent applications 229,635 and 206,101 cover certain 1,8-bridged 1,4-dihydro-4-quinolinones of the formula

Xs 0

X1 CO2H

2 (CR 1 R 2) m

(CR3R <I "-I ^ A

EVB

wherein is hydrogen, NO 2, 1-3C-alkyl or halogen, X 2 is halogen, 1-3C-alkyl, 1-3C-alkylsulphenyl or optionally substituted phenylsulphenyl, X 5 is hydrogen, halogen or methyl.

U.S. Patent 4,774,246 discloses certain substituted 1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -quinoline-3-carboxylic acids of the general formula

S O

rxrc-oRi l i

F R

U.S. Patent 4,704,459 describes a process for the preparation of certain 1-substituted aryl-1,4-dihydro-4-oxonaphthyridine derivatives. . for the preparation of derivatives of the general formula • · · 0, Xy ψ

F

U.S. Pat. No. 3,94750 discloses certain 1,8-naphthyridine derivatives of the general formula rpoir

RlNH

U.S. Patent 4,571,396 relates to certain naphthyridine, quinoline and benzoxazinecarboxylic acids having a crosslinked side chain at the 7-position.

Co-pending U.S. Patent Application 080,113 discloses certain naphthyridine, quinoline and benzoxazine carboxylic acids having a crosslinked side chain at the 7-position and hydrogen, fluorine or amino at the 5-position.

The references indicate that these compounds have antibacterial activity.

Also antibacterial is a compound of formula I R30 fsAX'c 00ri

XXJ

r2 or a pharmaceutically acceptable acid addition or base salt thereof, wherein Z is 4 P4750 NR5R </> (CR5R6) n_R4-Nn- or 1- \ v _ / [/ _ / "

Rn * Rn 'r «-nQ ~ \ - - <Z> - r, ~ <Xn- r," nSn_ << D- * s N ^ N— a wherein R4 is hydrogen, alkyl having 1 to 4 carbon atoms or 3 Cycloalkyl of -6 carbon atoms, R 6 is hydrogen, hydroxyl, alkyl of 1 to 4 carbon atoms, phenyl or phenyl substituted by halogen, alkyl or alkoxy, n • · · is an integer from 0 to 4, R 5 and R 6 are each independently hydrogen, lower alkyl or cycloalkyl, X is CH, CF, CC1, CBr, N, CCF3, CNH2, CNO2, CR or COR ", wherein R is lower alkyl and RM is hydrogen or lower alkyl, R3 is lower, straight chain, branched or unbranched; cyclic alkyl having 1 to 3 carbon atoms, R 2 is alkyl having 1 to 4 carbon atoms, l 5 94750 vinyl, haloalkyl, hydroxyalkyl having 2 to 4 carbon atoms. alkyl, cycloalkyl of 3 to 6 carbon atoms, phenyl or phenyl substituted by halogen, alkyl, NH 2 or OH is hydrogen, alkyl of 1 to 6 carbon atoms or a cation.

Preferred antibacterial compounds of formula I are those wherein X is CH, CF, CCl or N, R 2 is cyclopropyl, ethyl or 2,4-difluorophenyl, R 1 is methyl, ethyl, isopropyl or cyclopropyl, R 1 is hydrogen or a pharmaceutically acceptable a base salt such as a metal or amine salt, Z is (CRsR6) n '• -ψ- p- -

R 11 * wherein R 4 is hydrogen or methyl, R 'is hydrogen or methyl, n is 0 or 1, R 5 and R 6 are each independently hydrogen or methyl.

.. Particularly preferred are compounds wherein Z is a group

/ -v / -V

HN N - CH3N ^ N

i. ch3% x) - \ _ HN N— HN.

ciC CH3 6 94750 CH3 * ”20-. - u-, -O-. "2C.

fXCH3 / CV

JL / e-, 101CH3 L / _ - h2n -St>, - ‘· ΧΓ-

The most preferred compounds are those wherein X is CH, CF, CC1, R2 is cyclopropyl, R3 is CH3, Et, R3 is H and Z is // V H2NV ^ HN N-HN N-IN- or CH LN-) / 'N / CH3; Particularly preferred antibacterial compounds are: • 7,94750 1-cyclopropyl-6,8-difluoro-1,4-dihydro-5-methyl-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylic acid; 7- (3-amino-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid; 1-cyclopropyl-7- [3 - [(ethylamino) methyl] -1-pyrrolidinyl] -6,8-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid; 7- [3- (aminomethyl) -3-methyl-1-pyrrolidinyl] -1-cyclopropyl-6,8-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid; l-cyclopropyl-6,8-difluoro-l, 4-dihydro-5-methyl-7- [3-methyl-l-piperazinyl] -4-oxo-3-kinoliinikarboksyyli acid; l-cyclopropyl-6-fluoro-l, 4-dihydro-5-methyl-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylic acid; 1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-7- (3-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid; 7- (3-amino-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid; 6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-5-methyl-7- (3-methyl-1-piperazinyl-4-oxo-3-quinolinecarboxylic acid; 7- (3-amino- 1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid; 7- [3- (aminomethyl) -3-methyl- 1-Pyrrolidinyl] -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid; 7- [3- (endo-amino) -8- azabicyclo [3.2.1] oct-8-yl] -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, and pharmaceutically acceptable acid addition thereof or base salts.

8,94750 Intermediates in the preparation of the compounds described above include the following: 1-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid ethyl ester, 2.3.4.5-Tetrafluoro- 6-methyl-benzoic acid; 2.3.4.5-tetrafluoro-6-methylbenzoyl chloride; ethyl-3- (2,3,4,5-tetrafluoro-6-methylphenyl) -β-oxoprosta-panoaatti; ethyl (2,3,4,5-tetrafluoro-6-methylbenzoyl) -3-ethoxy-acrylate; 2- (2,4,5-trifluoro-3-trimethylsilylphenyl) -4,4-dimethyl-2-oxazoline; ethyl-2- (2,3,4,5-tetrafluoro-6-methylbenzoyl) -3-fal-lopropyyliaminoakrylaatti; 2- (2,4,5-trifluoro-6-methyl-3-trimethylsilylphenyl) -4,4-dimethyl-2-oxazoline; 2- (2,4,5-trifluoro-6-methylphenyl) -4,4-dimethyl-2-oxazoline; 2- (3-chloro-2,4,5-trifluoro-6-methylphenyl) -4,4-dimethyl-methyl-2-oxazoline; 2- (3-bromo-2,4,5-trifluoro-6-methylphenyl) -4,4-dimethyl-li-2-oxazoline; 2- (2,4,5-trifluoro-3-hydroxy-6-methyl-phenyl) -4,4-dimethyl-methyl-2-oxazoline; 2- (2,4,5-trifluoro-6-methyl-3-nitrophenyl) -4,4-dimethyl-li-2-oxazoline; 2- (2,4,5-trifluoro-3,6-dimethylphenyl) -4,4-dimethyl-2-oxazoline; 2- [2,4,5-trifluoro-3- (trifluoromethyl) -6-methylphenyl] -4,4-dimethyl-2-oxazoline; 2,6-dichloro-5-fluoro-4-methyl-3-pyridiinikarboksyyli acid; 3-chloro-2,4,5-trifluoro-6-methylbenzoic acid; 3-bromo-2,4,5-trifluoro-6-methylbenzoic acid; 2,4,5-trifluoro-6-methyl-3-nitrobenzoic acid and 2,4,5-trifluoro-3,6-dimethylbenzoic acid.

Il 94750 o

Compounds of formula I.

R3 O

f ^ Mn / C00Ri

Xm r2 wherein R1, R2, R3, R4, R5, R8, Z, n and R 'are as defined above can be prepared by a process wherein the compound of formula II

R3 O

: xYr COORi L χ N R 2 is reacted with an amine corresponding to the group Z, wherein all residues have the same meaning as in formula I above and L is a leaving group which may preferably be fluorine or chlorine.

This invention relates to a process for the preparation of compounds. having the formula • · «• a

R

Jx ^ P ^ COOH

Λ *,

B

* wherein R is alkyl, wherein in process (a) a compound of formula 10 94750 Λ xc is reacted with a base and trimethylsilyl chloride to produce a compound of formula

SiMe3 (b) this compound is reacted with a base and an alkyl halide to produce a compound of formula X *?

SiMe3 (c) The SiMe3 group is removed and (d) the resulting compound is hydrolyzed.

The naphthyridines of formula I can be prepared by (a) reacting a compound of formula ti 11 94750 'rxY' with

C ^ N ^ t T

R 2 is reacted with oxalyl chloride and dimethylformamide and the reaction is quenched with an alcohol to give the corresponding ester of the formula 'n-c 1 N 2 * r r 2 (b) the double bond is reduced to give a compound of formula χύ 1; (c) treating the compound obtained in step (b) with a base, followed by • preparation of a methyl iodide alkylated compound of formula

CH3 o O

r2 (d) is re-bonded and the resulting naphthyridine is reacted with the desired amine by known methods.

12 94750

The syntheses of the starting materials of formula II are described in the following schemes.

Scheme 1 shows the preparation of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-alkyl-4-oxo-3-quinolinecarboxylic acid.

F F

III IV

R 0 'RO Q

FvJvC0 ^ H 11 * Q yC ° 2 r T cic-cci Γ B C1 Q <fA ^ f dmf. f '^ Y ^ f COzEt -

F F

V VI

R O 0 R O O

F HC (OEt) 3 F ilx A ™ 2

Yjf '^ OEt ac2o YYy® Etoa F ^ F F * ^ Y ^ F ^ OEt

F F

VII VIII

. R O O R O O

as ΓχΥ ^ ° κ i> hci

F F A F A

IX X

II

13 94750 R ° o;) ^ ν .....

F λ

XI

In Scheme 1 above, 2-Penta-fluorophenyl-4,4-dimethyl-2-oxazoline of formula III is reacted with alkyllithium at -20 ° C to + 25 ° C to give 2- (2.3 ° C) of formula IV. (4,5-Tetrafluoro-6-alkylphenyl) -4,4-dimethyl-2-oxazoline, which is hydrolyzed under acidic conditions (preferably by refluxing under cooling with dilute hydrochloric acid), gives the corresponding benzoic acid of formula V. The compound of formula V is reacted with oxalyl chloride and the product is condensed with the dianion of monoethyl malonate (prepared from monoethyl malonic acid and n-butyllithium in THF) to give the keto ester of formula VII. This keto ester is treated with triethyl orthoformate in acetic anhydride to give an adduct of formula VIII. Reaction of a compound of formula VIII with cyclopropylamine in tert-butanol or ether yields an enamine of formula IX, other primary amines can be used in this reaction, such as aliphatic amines (ethylamine, etc.) and aromatic amines (p-fluoro). -aniline, 2,4-difluoroaniline, etc.). Most of the broadcast:. is reacted with potassium tert-butoxide in dry tert-butanol to form the desired cyclized compound of formula X which can be hydrolyzed by refluxing in acid to give the compound of formula XI.

14 94750

Scheme 2 depicts the syntheses of 5-alkyl, 8-X-quinolines (X * F).

XC —- XII CH * C1 *

XIII

ΎΎ ^ 0 2 cisittej rrrK * *** F ^ V ^ F STEP 4

XIV

'JJ &' JJ &

F ^^ S ^ F DMF / HjO FJv ^ kF

SiMej * VI 100 'XVII

F ^ H Kl ^. ^ XVIII ^ «s ~ 3T ^ r ^ #c .....; ΦΥ · FY-KAo C1 C1 ^

F \ ^ F V

SiMej R R O O

-1 \ Br2 <> HCl ^ CO, fJyUvoH

m ° * | \ «" O "c ,. A ^ r ~~ r \ V

,. - \ Bt Br A

1 | HC1 I XXI XXII

: 'v TFA

xr - -fr- F ^ | ' OH OR 1

NO, / A

XXIII XXIV

XXV

R O O (R - H, CH 2) '' tV / '”· f- ^ V ^ n ^ xxvi N (Ri> 2 / ^ (Ri - O, H)

II

15 94750

In Scheme 2 above, the acid of formula XII is converted to its acid chloride by reaction with oxalyl chloride and the acid chloride is treated with 2-amino-2-methyl-1-propanol N- (2-hydroxy-1,1-dimethylethyl) -2,4,5-tri- to give fluorocarboxamide (a compound of formula XIII). This amide is cyclized to the essential intermediate oxazoline of formula XIV by reaction with thionyl chloride in chloroform. The compound of formula XIV is then treated with a base, preferably lithium diisopropylamide, in THF or ether at -78 ° C and quenched with trimethylsilyl chloride to give the silylated oxazoline of formula XV.

The compound of formula XV is treated with a base (again preferably lithium diisopropylamide) in THF or ether at 0-20 ° C, after which the reaction is quenched with alkyl iodide to give, after further work up, the alkylated intermediate of formula XVI. Removal of the trimethylsilyl group is accomplished by treatment with cesium fluoride in aqueous DMF, the resulting compound of formula XVII is hydrolyzed to the corresponding benzoic acid of formula XVIII by refluxing in dilute hydrochloric acid. This benzoic acid is converted to 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-alkyl-4-oxo-3-quinolinecarboxylic acid using the method previously described in Scheme 1.

Alternatively, the silylated intermediate of formula XVI can be converted to various 3-substituted compounds by an "ipso" reaction on the trimethylsilyl group. For example, a compound of formula XVI is reacted; chlorine in the presence of iron powder, followed by hydrolysis at reflux in dilute acid to give 3-chloro-2,4,5-trifluoro-6-alkylbenzoic acid of formula XIX, this acid being treated as described above to give a solid of formula XX. to obtain nolin. Similarly, 16,94750 oxazoline of formula XVI is treated with N-bromosuccinimide in chloroform (or pyridinium bromide perbromide in dichloromethane) to give the corresponding 3-bromooxazoline, which is hydrolyzed and prepared to give a compound of formula XXII. Reaction of an intermediate of formula XVI with lead tetraacetate and trifluoroacetic acid followed by acid hydrolysis affords 2,4,5-trifluoro-3-hydroxy-6-alkylbenzoic acid of formula XXIII; the phenol can be converted to the methyl ether by reaction with methyl iodide and potassium carbonate in acetone. This 2,4,5-trifluoro-3-methoxy-6-alkylbenzoic acid is converted to 8-methoxyquinoline of formula XXIV (where R = CH 2), further treatment with HBr cleaves off the methyl ether to give the corresponding 8-hydroxyquinoline of formula XXIV (where R = H). Finally, nitration of a silylated compound of formula XVI with nitric acid in sulfuric acid and hydrolysis of the resulting compound affords nitric acid of formula XXV which is further treated to give 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-alkyl of formula XXVI. 8-nitro-4-oxo-3-quinolinecarboxylic acid (where R 1 = O). Reduction of the nitro group to the amino group can be done using Raney nickel to give a quinoline of formula XXVI (where R 1 = H).

• i

• f I I

• »

II

17 94750

Scheme 2A shows an alternative method for preparing 5-alkyl, 8-chloroquinolines.

vk o n-4t 2. CI3CCCI3 ΓγγΑ '° 2i R? Ä

F F F '^ V' ^ F

Cl

XIV XXXVIII

R f F 2 J 11 ° 11 HCl Cl Tl

XXXiX XIX

R O O

FxxVk ° H

, ·· ci A

XX

In Scheme 2A above, the oxazoline of formula XIV is treated with a base, preferably lithium diisopropylamide, in THF at -78 ° C and quenched with hexachloroacetone to give the chlorooxazoline of formula XXXVIII. The compound of formula XXXVIII is again treated with a base, preferably lithium diisopropylamide, in THF at 0 ° C and quenched with alkyl iodide to give, after further work-up, an intermediate of formula XXXIX. Hydrolysis of the oxazoline moiety by refluxing in dilute hydrochloric acid affords the benzoic acid of formula XIX. This acid is prepared as 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-alkyl-4-oxo-3-quinolinecarboxylic acid of formula XX.

li • · «19 94750

Scheme 3 depicts the syntheses of 5,8-dialkylquinolines.

n ^ C

E \ 1- LDA F JL. 1. LDA

Yjf 0 2 * ** VV0 2. R-X

fA, Af "

R

XIV XXVII

R 'N R' jl F vJ \ ^ c ° 2h to normal | 0 «f HCl Il ^ P3311

F ^ y ^ F F / y'F

R R

xxviii xxix R * o O where R is l / and R · = CH3, Et, F. .Js. JL propyl.

Il II 0H

A

xxx

In Scheme 3, an oxazoline of formula XIV (prepared in Scheme 2) is treated with a base, preferably lithium diisopropylamide, in THF at -78 ° C and quenched with an alkyl halide (such as methyl iodide, ethyl iodide, etc.) to give a compound of formula XXVII. a compound wherein R is alkyl. Further treatment with a base (preferably lithium diisopropylamide) in ether at 0 ° C followed by the addition of an alkyl halide gives dialkyloxazolines such as compounds of formula XXVIII. The intermediates are hydrolyzed and the work-up is continued as described above to give 5,8-dialkyl-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of formula XXX.

II

21 94750

Scheme 4 depicts the synthesis of 5-alkylnaphthyridines.

R

F \ A / C02Et YT J £ L · -SL · Yjf

Cl ^ N ^ Cl CI ^ Kj ^ CI

XXXI XXXII

o o

Il II

1) C1C-CC1 Λ 1) AC2O,

R 2) 002 ^ HC (OEt) 3 1) -f-OK

I I HCl FY * YC ° 2H Q <CO 2 Et 2> A / nH, 2, <) HCl

Cl ^ N ^ Cl XXXIII R O O

v XXX where R = CH 3, Et, OH propyl.

c'A

XXXIV

OR O O

i H H U

1) ClOCCl FYYC ° 2H 2> H2NXoh soci2 phyl °

Cl ^ N ^ Cl Cl ^ N ^ Cl

XXXV XXXVI

lm RMgBr ^ i \ HCl [FnJv.CO2H

Cl ^ N ^ Xl Cl "'n Cl

XXXIII

XXXVII

22 94750

In Scheme 4 above, a pyridine ester of formula XXXI (Chem.Pharm.Bull. 35 (1987), p. 2280) is reacted with a base such as lithium diisopropylamide in THF at low temperature, followed by reaction with an alkyl halide such as ethyl iodide. or with methyl iodide, hydrolysis of the ester in dilute acid gives a compound of formula XXXIII.

alternatively, the ester of formula XXXI can be hydrolyzed in dilute acid to give the pyridine acid of formula XXXV, which in turn is converted to the corresponding oxazoline in the usual manner (see Scheme 2). This oxazoline (compound of formula XXXVI) is reacted with an alkyl lithium (such as methyllithium), after which the compound is re-aromatic with DDQ or chloraniline. This part of the reactions gives the alkyl-substituted pyridine of formula XXXVII, which, after acid hydrolysis, gives the required intermediate of formula XXXIII.

The compound of formula XXXIII is prepared as 5-alkyl-7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid in a conventional manner.

II

23 9 4 7 5 0

Scheme 5 'rxV'- —- rrxV ^ C1 «f

* A, A

NaBH3CN

N + CH 3 O 0 0

FrVSA ° ^ υ sBuLi thf "7 ° 'c Fviv ^ vJlxo · ^ -

C1 N N 2) CH3I Cl ^ N ^ tT

, A, A

1) NaH

2) PhSeCl 3> h 2 O 2

ί ** 3 j? n / s. NHBOC CH3 O O

AEt3N, CH3CN \ f N i

V, A

nh2 24 9 4 7 5 0 Also prepared by this method

Ch3 o o O Λ

B

B

In Scheme 5 above, the known naphthyric acid (U.S. Patent 4,663,457, 1987) is reacted with oxalyl chloride and DMF, after which the reaction is quenched with absolute ethanol to give ester 2. Reduction of the double bond is performed with sodium cyanoborohydride to give compound 2 / then treated with sec-butyllithium at -78 ° C. This dianion is treated with methyl iodide to give the alkylated intermediate 4. The double bond is re-introduced into the compound by a series of reactions: first treated with sodium hydride, then phenylselenyl chloride is added and oxidized with hydrogen peroxide. The final ester 5 can then be reacted with various amines in the usual manner.

f «» • · «

II

25 9 4 7 5 0

Scheme 6 shows the syntheses of 5-alkyl-8-trifluoromethyl derivatives.

1. LDA / THF

FS ^ yBr -78'C F \ ^ vN ^ Br HF / SF «

2. CO 2 / Et 2 O F ^ 'y' ^ F 120 * C

84% CO 2 H 8hr * 88% XL 0 0

Il II

o 1. C1C-CC1

Fy ^ YBr 1. BuLi / Et2O FV "Y ^ ° H NH2-f-CH3 ΛΑ ~ r ~ ^ —- Al, - ^ CF3 89% 'CFs

XLI

XLII

o N * ^ C

F ___, CH3 1. S0C12 P ^ I / 1. LDA

'V *! # ^ Jp ^ NH-AcH3 2. NaH y ^ f ° 2' RI

fAjAf Loh f ^ S

: CF3 cf3

XLIII XLIV

R R o O

_- F where R = CH3 Et F ^ y ^ F f ^ 5 | Ns? cf3 cf3 rx

XLV XLVI

26 94750

At the beginning of Scheme 6, 2,4,5-trifluorobromobenzene is treated with a base, preferably lithium diisopropylamide, in THF at -78 ° C. This anion reaction is quenched with carbon dioxide to give, after acidification, the acid of formula XL. This acid is reacted with HF / SF4 at 120 ° C to give the trifluoromethyl derivative of formula XLI. The necessary acid functionality is provided by halogen-metal exchange (preferably with butyl ether in ether at -78 ° C), after which the carbon dioxide quenches the reaction and the reaction mixture is acidified. The compound of formula XLII is then treated with oxalyl chloride to form the acid chloride and added to 2-amino-2-methyl-1-propanol in chloroform at 0 ° C to prepare the hydroxyamide of formula XLIII. The cyclization to the key intermediate oxazole of formula XLIX occurs in the usual manner, i. by treatment with thionyl chloride followed by sodium hydride. Deprotection of a compound of formula XLIV with lithium diisopropylamide at -78 ° C and reaction of the anion with an alkyl iodide affords a fully substituted oxazoline of formula XLV which can be prepared to the target quinoline of formula XLVI using previously published methods.

* • <

The alkyl groups present in the invention are both straight-chain and branched carbon chains containing 1 to 6 carbon atoms. Typical such groups include methyl, ethyl, propyl, isopropyl and the like.

The term haloalkyl means halogen-substituted, straight-chain or branched carbon chains having 2 to 4 carbon atoms. One skilled in the art will recognize that a halogen substituent cannot be present on the α-carbon atom of the chain. Typical such groups include β-fluoroethyl, β-chloroethyl, O, β-dichloroethyl, β-chloropropyl, O-chloro-2-propyl, 7-iodobutyl and the like.

27,. 94750 The term halogen means fluorine, chlorine, bromine and iodine unless otherwise stated.

The following non-limiting examples illustrate the process of the invention and closely related processes for the preparation of other starting materials and intermediates, as well as further antibacterial compounds.

The required method is described in Examples K, L, O and R.

Preparation of starting materials Example A

2- (2,3,4,5-tetrafluoro-6-methylphenyl) -4,4-dimethyl-2-oxazoline

A solution of 21.2 g (80.0 mmol) of 2- (pentafluorophenyl) -4,4-dimethyl-2-oxazoline (Bull.Chem.Soc. Jpn., 57, 225 (1984)) in 300 ml in dry ether, cooled to -20 ° C under argon and treated with 60 mL of 1.6 M methyllithium (96.0 mmol). The solution was stirred at -20 ° C for two hours, then stirred at room temperature overnight. The mixture was diluted with water and the organic layer was dried over magnesium sulfate and concentrated to give 20.8 g of the title compound as an orange oil.

Example B

2,3,4,5-tetrafluoro-6-metvvlibentsoehappo

A mixture of 20.5 g (73.4 mmol) of 2- (2,3,4,5-tetrafluoro-6-methylphenyl) -4,4-dimethyl-2-oxazoline in 200 ml of 6 N hydrochloric acid , was refluxed for 18 hours, then cooled to room temperature. The solution was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated. The residue was suspended in water which was basified (pH

11) 1 M sodium hydroxide and extracted with ether, the aqueous 94750 28 siphase was acidified (pH 2) with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to give 8.4 g of the title compound as a tan solid, m.p. was 80-82 ° C.

Example C

2.3.4.5-Tetrafluoro-6-methylbenzoyl chloride

A solution of 8.2 g (39.4 mmol) of 2,3,4,5-tetrafluoro-6-methylbenzoic acid, 6.0 g (47.2 mmol) of oxalyl chloride and 100 ml of dichloromethane was treated with three drops of DMF was added. The solution was stirred for 3 hours, after which it was concentrated to give 8.8 g of the title compound as a yellow liquid. The product was used as such in the next step.

Example D

Ethyl 3- (2,3,4,5-tetrafluoro-6-methylphenyl) p-oxopropanoate

A solution of 10.1 g (76.5 mmol) of malonic acid monoethyl ester bipyridyl (catalytic) and 200 ml of dry THF was cooled to -35 ° C under an argon atmosphere, treated with 52 ml of 1.5 M n-butyllithium (78 mmol) and warmed to -5 ° C. To this mixture was added 52 mL of 1.5 M n-butyllithium (78 mmol) until a pale pink color persisted for 10 minutes. The suspension was cooled to -78 ° C and treated with a solution of 8.8 g (38.8 mmol) of 2,3,4,5-tetrafluoro-6-methylbenzoyl chloride in 100 mL of dry THF. The reaction mixture was stirred at -78 ° C for 45 minutes, then warmed to -35 ° C and poured into a mixture of ice and 1N hydrochloric acid (77 mL). The organic layer was washed with 5% sodium bicarbonate solution, 3 M hydrochloric acid. . polla and water and dried over magnesium sulfate. Konrad

II

Concentration of 29 94750 gave an orange oil which was chromatographed on silica gel (E. Merck 230-400 Mesh) eluting with a 80:20 mixture of chloroform and ethyl acetate to give 8.2 g of the title compound.

Example E

Ethyl 2- (2,3,4,5-tetrafluoro-6-methylbenzoyl-3-ethoxyacrylate)

A solution of 8.1 g (29.1 mmol) of ethyl 3- (2,3,4,5-tetrafluoro-6-methylphenyl) -O-oxopropanoate, 7.2 g (43.3 mmol) triethyl orthoformate and 70 ml of acetic anhydride, refluxed for 3.5 hours. The solution was cooled to room temperature and concentrated under high vacuum to give 9.1 g of the title compound.

The product was used as such in the next step

Example F

Ethyl 2- (2,3,4,5-tetrafluoro-6-methylbenzoyl) -3-cyclopropylaminoacrylate

To a solution of 9.0 g (27.0 mmol) of ethyl 2- (2,3,4,5-tetrafluoro-6-methylbenzoyl) -3-ethoxyacrylate in 30 ml of absolute ethanol at 5 ° C , 1.68 g (29.4 mmol) of cyclopropylamine were added. The mixture was stirred at 5 ° C for 1.5 hours and at room temperature for 2.5 hours. The solution was concentrated to an oil which was triturated with hexane to give a tan solid. The crude product was recrystallized from hexane to give 9.07 g of the title compound, m.p. was 72-74 ° C.

94750 30

Example G

Ethyl 1-cyclopropyl 6.7.8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylate

To a mixture of 9.05 g (26.3 mmol) of ethyl 2- (2,3,4,5-tetrafluoro-6-methylbenzoyl) -3-cyclopropylaminoacrylate in 100 ml of dry tert-butanol was added a slurry of 3.25 g (29.0 mmol) of potassium tert-butoxide in 20 ml of dry tert-butanol, and the mixture was stirred at 60 ° C for 4 hours. The suspension was cooled to room temperature and concentrated to a paste which was partitioned between dichloromethane and 1N hydrochloric acid. The organic layer was separated, dried over magnesium sulfate and concentrated. Recrystallization from a mixture of ethyl acetate and hexane gave 4.70 g of the title compound, m.p. was 176-177 ° C.

Example H

l-cyclopropyl-6,7. β-Trifluoro-1,4-dihydro-5-roethyl-4-oxo-3-quinolinecarboxylic acid

A mixture of 4.6 g (14.1 mmol) of ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylate 100 in 6 M hydrochloric acid, refluxed for 4 hours. The solution was cooled to room temperature and the solids were filtered, washed with water and dried to give 3.9 g of the title compound, m.p. was 234-235 ° C.

In a similar manner, 1-cyclopropyl-5-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 1,5-dicyclopropyl-6,7,8-trifluoro-1 , 4-dihydro-4-oxo-3-quinolinecarboxylic acid.

II

«• 4 31 94750

Example I

N- (2-hydroxy-1,1-dimethyl) -2,4,5-trifluoro-benzamide

A solution of 19.4 g (110 mmol) of 2,4,5-trifluorobenzoic acid (JP 58,150,543 (Cl. C07C69) Sep. 7, 1983), 15.2 g (120 mmol) of oxalyl chloride and 250 ml of dichloromethane was treated with 4 drops of DMF and the mixture was stirred at room temperature for 4 hours. The mixture was concentrated to an oil and redissolved in 100 mL of dichloromethane. This solution was added dropwise to a solution of 19.6 g (240 mmol) of 3-amino-2-methyl-1-propanol in 200 ml of dichloromethane at 5 ° C, and the reaction mixture was stirred at room temperature overnight. The solids were filtered and the filtrate was washed with 5% sodium bicarbonate, 1 N hydrochloric acid and water. The organic layer was dried over magnesium sulfate and concentrated to give 24.5 g of the title compound, m.p. was 114-116 ° C.

Example J

2- [2,4,5-trifluorophenyl] -4,4-dimethyl-2-oxazoline

To a solution of 24.4 g (98.7 mmol) of N- (2-hydroxy-1,1-dimethylethyl) -2,4,5-trifluorocarboxamide in 200 mL of chloroform was added dropwise 25 mL (342 mmol) of thionyl chloride. The solution was stirred overnight at room temperature, then concentrated to half volume. The mixture was diluted with ether and the solid was removed by filtration. This solid was dissolved in water, basified (pH 8) with 10% sodium hydroxide and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to give 19.0 g of the title compound, m.p. was 53-54 ° C.

94750 32

Example K

2- (2,4,5-Trifluoro-3-trimethylsilyl) phenyl-4,4-dimethyl-2-oxazoline

A solution of 8.7 mL (62.1 mmol) of diisopropylamine in 100 mL of dry THF under argon was cooled to -78 ° C and treated with 28.3 mL (56.6 mmol) of diisopropylamine. 2.0 M n-butyllithium. The LDA solution was stirred at -78 ° C for 15 minutes. To this solution was added a solution of 11.8 g (51.5 mmol) of 2- (2,4,5-trifluorophenyl) -4,4-dimethyl-2-oxazoline in 50 mL of THF, and the reaction mixture was stirred once. hour at -78 ° C. To the reaction mixture was added 13 ml (102.5 mmol) of chlorotrimethylsilane, and the solution was warmed to room temperature. Water was added, the organic layer was dried over magnesium sulfate and concentrated. The crude product was chromatographed on silica gel (E.Merck 230-400 Mesh) eluting with a 80:20 mixture of chloroform and ethyl acetate to give 12.9 g of the title compound, m.p. was 71-72 ° C.

Example L

2- (2,4,5-Trifluoro-e-methyl-S-trimethylsilylphenyl) -4,4-dimethyl-2-oxazoline A solution of 0.64 ml (4.57 mmol) of diisopropylamine in 20 ml in dry THF under argon, cooled to -78 ° C and treated with 2.1 mL (4.20 mmol) of 2.0 N n-butyllithium The LDA solution was stirred at -78 ° C for 15 minutes, which then warmed to 0. To this solution was added a solution of 1.05 g (3.5 mmol) of 2- (2,4,5-trifluoro-3-trimethylsilylphenyl) -4,4-dimethyl-2 -oxazoline in 5 mL of THF, the reaction mixture was stirred at 0 ° C for 45 minutes, then quenched with 1.50 g (10.6 mmol) of methyl iodide, stirred at room temperature for 3 hours and diluted with water. The organic layer was washed

II

33,94750 in water, dried over magnesium sulfate and concentrated to give 1.00 g of the title compound as an oil.

In a similar manner, 1-cyclopropyl-5-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4- oxo-5-iso-propyl-3-quinolinecarboxylic acid.

Alternatively, the trimethylsilyl group was replaced with chlorine (Chem. Abstr. M / 20932 (1960)) or bromine (J. Am. Chem. Soc. 70, 433 (1948)) and the oxazoline was hydrolyzed to give 3-chloro-2,4,5- trifluoro-6-methylbenzoic acid and 3-bromo-2,4,5-trifluoro-6-methylbenzoic acid, respectively. From these intermediates, 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 8-bromo-1-cyclopropyl-6,7-difluoro-1 , 4-dihydro-5-methyl-4-oxo-3-kinoliinikar-acid.

In addition, the trimethylsilyl group was reacted with lithium tetraacetate / trifluoroacetic acid to add a hydroxyl group (Tet.Lett. 10, 853 (1974)) and was also reacted with nitric acid to add a nitro group (J. Chem. Soc. 498 (1957)).

Using conventional methods, the following compounds were prepared: 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-hydroxy-5-methyl-4-oxo-3-quinolinecarboxylic acid; 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-5-methyl-4-oxo-3-quinolinecarboxylic acid; 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-8-nitro-4-oxo-3-quinolinecarboxylic acid and 8-amino-1-cyclopropyl-6,7-difluoro-1, 4-dihydro-5-methyl-4-oxo-3-kinoliinikarboksyy1ihappo. 1 * 34 94750

Example M

7-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid

Ethyl 2,6-dichloro-5-fluoronicotinate (Chem.Pharm.Bull. 35 (6), 2280 (1987)) was treated with lithium diisopropylamide and quenched with methyl iodide to give, after further work-up, ethyl 2,6-dichloropropylamide. dichloro-5-fluoro-4-methylnicotinate. This compound was hydrolyzed to give the corresponding acid, which was worked up in the usual manner to give 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid. -lihappo. In a similar manner, 7-chloro-1-cyclopropyl-5-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid was synthesized.

Example N

2,4,5-Trifluoro-3,6-dimethylbenzoic acid 2- (2,4,5-trifluorophenyl) -4,4-dimethyl-2-oxazoline was also treated with lithium diisopropylamide followed by methyl iodide to give 2- (2,4,5- trifluoro-3-methyl-phenyl) -4,4-dimethyl-2-oxazoline. This intermediate, in turn, was treated with lithium diisopropylamide followed by methyl iodide to give 2- (2,4,5-trifluoro-3,6-dimethylphenyl) -4,4-dimethyl-2-oxazoline. Hydrolysis of oxazoline afforded 2,4,5-trifluoro-3,6-dimethyl-benzoic acid which was converted to 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5,8-dimethyl-4-oxo-3 -quinolinecarboxylic acid as usual.

* »Li 35 94750

Example O

2- (2,4,5-Trifluoro-6-methylphenyl) -4,4-dimethyl-2-oxazoline

A solution of 12.0 g (38.0 mmol) of 2- [2,4,5-trifluoro-6-methyl-3- (trimethylsilyl) phenyl] -4,4-dimethyl-2-oxazoline, 5 , 85 g (38.5 mmol) of cesium fluoride, 110 ml of dimethylformamide and 15 ml of water were stirred for 18 hours at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate, the organic phase was washed with water, dried over magnesium sulfate and concentrated to give 9.1 g of a liquid.

Example P

2- (3-chloro-2,4,5-trifluorophenyl) -4,4-dimethyl-2-oxazoline

A solution of 7.6 mL (54.2 mmol) of diisopropylamine in 100 mL of dry THF was cooled to -78 ° C under argon and treated with 20.5 mL (47.2 mmol). 2.3 M n-butyllithium and stirred for 15 minutes.

To this solution was added a solution of 10.3 g (45.0 mmol) of 2- (2,4,5-trifluorophenyl) -4,4-dimethyl-2-oxazoline in 100 mL of dry THF. The reaction mixture was stirred at -78 ° C for 45 minutes. To this mixture was added 26.5 g (100 mmol) of hexachloroacetone and the solution was warmed to room temperature. Water was added, the organic phase was washed with water, 1N hydrochloric acid and 5% sodium bicarbonate and dried over magnesium sulfate. Concentration gave a dark oil which was chromatographed on silica gel to give 7.05 g of the title compound as a yellow oil.

36 94750

Example O

2- (3-chloro-2,4,5-trifluoro-6-methyl-4,4-dimethyl-2-oxazoline

A solution of 5.5 mL (39.2 mmol) of diisopropylamine in 125 mL of dry THF was cooled to -78 ° C under argon and treated with 13.8 mL (31.7 mmol). 2.3 M n-butyllithium and stirred for 15 minutes.

To this solution was added a solution of 7.00 g (26.5 mmol) of 2- (3-chloro-2,4,5-trifluorophenyl) -4,4-dimethyl-2-oxazoline in 75 mL of dry THF. was added. The mixture was stirred at -78 ° C for 30 minutes and at 0 ° C for 60 minutes.

To this solution was added 11.3 g (79.6 mmol) of methyl iodide, and the mixture was stirred at room temperature overnight. Water was added, the organic phase was washed with 1 N Helium, 5% sodium bicarbonate and water. The solution was dried over magnesium sulfate and concentrated to an oil which was chromatographed on silica gel to give 6.3 g of a clear orange oil.

Example R

2,4,5-Trifluoro-6-methylbenzoic acid

A mixture of 9.1 g (37.4 mmol) of 2- (2,4,5-trifluoro-6-methylphenyl) -4,4-dimethyl-2-oxazoline in 200 ml of 6 M hydrochloric acid was refluxed overnight. after which it was cooled to room temperature. The solution was extracted with ethyl acetate, and the extract was washed with water, dried over magnesium sulfate and concentrated. The residue was suspended in water which was basified (pH 11) with 1 N NaOH, washed with ether and acidified (pH 2) with 1N HCl. The solution was extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and concentrated to give 5.8 g of the title compound, m.p. was 108-110 ° C.

•. .1 ·

II

37 94750

Example S

3-Chloro-2,4,5-trifluoro-6-methylbenzoic acid

As described in Example D, the title compound was prepared from 2- (3-chloro-2,4,5-trifluoro-6-methylphenyl) -4,4-dimethyl-2-oxazoline and 6 N hydrochloric acid. The desired acid was obtained as a tan solid, m.p. was 104-106 ° C.

Example T

2,4,5-trifluoro-6-methylbenzyl chloride

A solution of 5.8 g (30.5 mmol) of 2,4,5-trifluoro-6-methylbenzoic acid, 4.7 g (37.0 mmol) of oxalyl chloride and 100 ml of dichloromethane was treated with three drops of DMF. . The reaction mixture was stirred at room temperature for 2 hours, after which it was concentrated to give 6.3 g of the title compound as an oily solid. The product was used "as is" in the next step.

Example U

3-chloro-2.4.5-trifluoro-6-metwlibentsovvlikloridi

The title compound was prepared from 3-chloro-2,4,5-trifluoro-6-methylbenzoic acid and oxalyl chloride following the procedure described in Example F.

Example V

Ethyl-3-f2.4.5-trifluoro-6-metvvlibentsowli) -en-oxo-propanoate

A solution of 8.0 g (60.5 mmol) of bipyridyl monoethyl ester of roalic acid (catalytic) and 200 mL of dry THF was cooled to -35 ° C under argon and treated with 32 mL of 1.9 M n-butyllithium ( 60.8 .. mmol) and warmed to -5 ° C. An additional 32 mL of 1.9 M n-butyllithium was added to this suspension until a pale pink color persisted for 10 minutes. The mixture was cooled to -78 ° C. To this mixture was added a solution of 6.3 g (30.2 mmol) of 2,4,5-trifluoro-6-methylbenzoyl chloride in 75 mL of dry THF, and the reaction mixture was stirred at -78 ° C for one hour. . The solution was then warmed to -35 ° C, poured into a mixture of ice and 1N hydrochloric acid (70 ml) and extracted with ethyl acetate. The organic layer was washed with 5% sodium bicarbonate, 3 M hydrochloric acid and water and mixed with magnesium sulfate. Concentration gave an oil which was chromatographed on silica gel (E.Merck 230-400 Mesh) eluting with a 80:20 mixture of chloroform and ethyl acetate to give 7.2 g of the title compound.

Example W

Ethyl 3- (3-chloro-2,4,5-trifluoro-6-methylbenzoyl) -8-oxopropanoate

The procedure set forth in Example H was used to prepare the title compound from the dianion of a monoethyl ester of malonic acid and 3-chloro-2,4,5-trifluoro-6-methylbenzoyl chloride. The crude product was also chromatographed on silica gel to give the desired product as an orange oil.

Example X

Ethyl-2- (2.4.5-trifluoro-6-metvvlibentsovvli) -3-ethoxy-acrylate

A solution of 7.1 g (27 mmol) of ethyl 3- (2,4,5-trifluoro-6-methylbenzoyl) -8-oxopropanoate, 6.8 g (41 mmol) of triethyl orthoformate and 60 ml of acetic anhydride -ride, refluxed for 3 hours, cooled to room temperature and concentrated to give 8.4 g of the title compound. The crude product was used as such in the next step.

39 94750

Example Y

Ethyl 2- [3-chloro-2,4,5-trifluoro-6-methylbenzoyl] -3-ethoxyacrylate

Using the procedure set forth in Example J, the title compound was prepared from ethyl 3- (3-chloro-2,4,5-trifluoro-6-methylbenzoyl) -β-oxopropanoate, triethyl orthoformate and acetic anhydride.

Example Z

Ethyl 2- (2,4,4-trifluoro-6-methylbenzoyl) -3-cyclopropylaminoacrylate

To a solution of 8.3 g (26 mmol) of ethyl 2- (2,4,5-trifluoro-6-methylbenzoyl) -3-ethoxyacrylate in 30 ml of absolute ethanol at 5 ° C was added 1.64 g (29 mmol) cyclopropylamine. The reaction mixture was stirred at 5 ° C for 90 minutes and at room temperature for 2 hours.

The solution was concentrated to give a brown oil which was dissolved in hexane and reconcentrated to give a tan solid. Recrystallization from hexane gave 7.2 g of colorless crystals of m.p. was 69-72 ° C.

The following compounds were prepared in a similar manner from the appropriate ethoxyacrylate: a) ethyl 2- (3-chloro-2,4,5-trifluoro-6-methylbenzoyl) -3-cyclopropylaminoacrylate. mp 77-80 ° C; b) ethyl 2- (2,3,4,5-tetrafluoro-6-methylbenzoyl) -3-ethylaminoacrylate. hygroscopic solid; c) ethyl 3- (2,4-difluoroanilino] -2- (2.3.4.5-tetrafluoro-6-methylbenzoyl} acrylate, viscous oil; d) ethyl 3- (2-bromoethylamino) -2- (2.3.4.5-tetrafluoro -6-methylbenzyl) acrylate, mp 95-100 DEG C. e) ethyl 3- (ethylamino) -2- (2,4,5-trifluoro-6-methylbenzoyl) acrylate. hygroscopic solid; 40 94750 f) ethyl 3- (2,4-difluoroanilino) -2- (2,4,5-trifluoro-6-methylbenzyl acrylate, mp 79-83 ° C) and g) ethyl 3- (2-bromoethylamino) - 2- (2.4.5-trifluoro-6-metwlibentsowliiakrvlaatti.

Example AA

Ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate

A solution of 7.2 g (22 mmol) of ethyl 2- (2,4,5-trifluoro-5-methylbenzoyl) -3-cyclopropylaminoacrylate in 100 ml of dry tert-butanol was treated portionwise with 2 portions. , 8 g (25 mmol) of potassium tert-butoxide and the reaction mixture were stirred at 60 ° C for 5 hours. The suspension was cooled to room temperature and concentrated. The residue was partitioned between dichloromethane and 1N hydrochloric acid, the organic phase was washed with water, dried over magnesium sulfate and concentrated. The crude product was slurried in boiling ethanol, filtered and air dried to give 4.2 g of the title compound.

The following compounds were prepared in the same manner and purified as indicated: a) ethyl 8-chloro-1-chloropropyl-6,7-difluoro-1,4-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylate; mp 151-153 ° C (chromatographed on silica gel); b) ethyl 1-ethyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylate. mp 185-187 ° C (recrystallized from ethyl acetate); c) ethyl 1- (2-bromoethyl) -6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylate. mp 149-150 ° C (recrystallized from ethyl acetate / hexane); 41 94750 d) ethyl 1-ethyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolecarboxylate. mp 189-191 ° C.

Example BB

Ethyl 6.7.8-trifluoro-1,4-dihydro-5-methyl-4-oxo-1-vinyl-3-quinolinecarboxylate

A rapidly stirred suspension of 1.98 g (5.08 mmol) of ethyl 1- (2-bromoethyl) -6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo- 3-Quinolinecarboxylate, 3.50 g (25.3 mmol) of ground potassium carbonate and 40 mL of DMF was heated at 80 ° C under argon for 4 hours. The suspension was concentrated and the residue partitioned between methylene chloride and water. The organic layer was dried over magnesium sulfate and concentrated to give 1.52 g of the title compound as a DMF complex, m.p. was 150-152 ° C.

Example CC

Ethyl 6,7,8-trifluoro-1- (2,4-difluorophenyl) -1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylate

To a cold (5 ° C) solution of 2.77 g (6.64 mmol). ethyl 3- (2,4-difluoroanilino) -2- (2,3,4,5-tetrafluoro-6-methylbenzoyl) acrylate in 60 ml of dry THF, 0.32 g of 60% sodium hydride was added. The solution was stirred overnight at room temperature, after which it was concentrated to an orange foam. The residue was partitioned between methylene chloride and 1 N HCl. The organic phase was washed with water, dried over magnesium sulfate and concentrated to an orange solid which was recrystallized (ethyl acetate / hexane) to give 1.55 g of the title compound, m.p. was 152-154 ° C.

I · 42 94750

Example DP

Ethyl 6,7-difluoro-1- (2,4-difluorophenyl) -1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylate The procedure described in Example AA was used to prepare the title compound ethyl 3- (2, 4-difluoroanilino) -2- (2,4,5-trifluoro-6-methylbenzoyl) acrylate, m.p. was 161-164 ° C.

Example EE

l-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-kinoliinikarboksvvlihappo

A suspension of 4.1 g (13.3 mmol) of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate in 150 ml of 6N hydrochloric acid , was refluxed for 6 hours, then cooled to room temperature. The solids were filtered, washed with water and ether and dried to give 3.2 g of the title compound, m.p. was> 300 eC.

The following compounds were prepared in a similar manner: a) 1-Ethyl-6,7-8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid. mp 199-201 ° C; > b) 1-ethyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid. mp > 300 ° C; c) 8-Chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid. mp 212-214 ° C.

Example FF

7-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro- 4-Oxo-1,8-naphthyridine-3-carboxylic acid (U.S. Patent 4,663,457) 43,94750 (20.0 g, 71 mmol) and dimethylformamide (0.5 mL) were added to dichloromethane (750 mL) to give a tan slurry. To this slurry was added oxalyl chloride (7.4 mL, 85 mmol) over one minute and the reaction mixture was stirred for 90 minutes, then an additional 2.0 mL of oxalyl chloride was added and stirring was continued for 60 minutes. To the resulting brown solution was added absolute ethanol (4.3 mL, 78 mmol) and the mixture was stirred for 4 h, then cooled to 0 ° C and stored overnight. The reaction mixture was warmed to room temperature and an additional 2 mL of absolute ethanol was added and stirring was continued for 3 hours. The reaction mixture was evaporated to a brown solid. The solid was heated in THF, filtered and cooled to 0 ° C. The formed crystals were collected and dried to give the title compound (11.1 g, 50%).

Example GG

7'-1-N-1-5-methyl-6-fluoro-1,2,3,4-tetrahydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ester. 3

The compound prepared in Example FF (3.0 g, 9.6 mmol) and sodium cyanoborohydride (0.7 g, 10 mmol) were suspended in absolute ethanol (200 mL) and 3 drops of concentrated HCl were added to give a bright yellow solution. The reaction proceeded and was monitored by TLC (silica gel, CH 2 Cl 2 / CH 3 OH, 9: 1, v / v), if necessary concentrated HCl was added to maintain the progress of the reaction.

After 6 hours, the reaction was quenched by adding • to 300 mL of water. The reaction mixture was extracted several times with 0-2012: 1ΐ3 and the combined organic layers were dried, filtered and evaporated to a yellow solid. This solid was filtered through silica gel with CH 2 Cl 2 and after evaporation the solid was crystallized from isopropyl ether. The collected crystals were further purified by column chromatography on silica gel, 44,94750 eluting with CH 2 Cl 2 to give the title compound (2.2 g, 73%).

The following compound was prepared in a similar manner: a) 7-Chloro-6-fluoro-1- (2,4-difluoro-phenyl) -1,2,3,4-tetrahydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ester.

Example HH

7-Chloro-1-cyclopropyl-6-fluoro-1,2,3,4-tetrahydro-5-methyl-4-oxo-1. 8-Naphthyridine-3-carboxylic acid ester,

Compound GG (4.5 g, 14 mmol) was dissolved in THF (170 mL) and cooled to <-70 ° C. Sec-butyllithium (22.2 mL, 28 mmol, 1.3 M) was then added dropwise over 30 minutes, keeping the internal temperature <-70 ° C throughout. After stirring at -70 ° C for 1 h, methyl iodide (0.9 mL, 14 mmol) was added and the reaction mixture was stirred at -70 ° C for 7 h. The reaction vessel was transferred to a Dewar with dry ice / isopropanol and allowed to stand for 17 hours. At the end of this period, the reaction temperature had risen to -25 ° C. The reaction was quenched by the addition of saturated NH 4 Cl solution (50 mL) and the reaction mixture was diluted with an equal volume of CH 2 Cl 2. The organic layer was separated and washed with saturated NaCl solution, dried, filtered and evaporated to an oil. This oil was purified by column chromatography on silica gel, eluting with CH 2 Cl 2 to give, after combining and evaporating the appropriate fractions, the title compound (3.91 g, 85%).

li 11 45 94750

Example II

Ethyl 7-chloro-1-chloropropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid Using the method of Reich et al., J. Amer. Chem. Soc., (1975) 97, 5434, the compound prepared in Example HH (0.68 g, 2.1 mmol) was converted to the title compound (0.44 g, 64%). Purification was performed by crystallization from isopropyl ether.

Example JJ

3-bromo-2.5.6.-trifluorobenzoic acid

To a solution of diisopropylamine (8.89 g, 88 mmol) in THF (80 mL) stirred under nitrogen at 0 ° C was added n-butyllithium (2.6 M in hexane) over 10 minutes. , 32 mL, 84 mmol). After 10 minutes at 0 ° C, the solution was transferred via catheter over 40 minutes to a solution of 2,4,5-trifluorobromobenzene (16.88 g, 80 mmol) in THF (200 mL) and stirred under nitrogen. At -78 ° C. After 15 minutes, the solution was blown through the catheter over about 2 minutes into a slurry of co 2 (about 200: mL) in ether (400 mL) with vigorous stirring.

After CO 2 evaporated, the slurry was washed with dilute HCl (1 M, 200 mL) and water (100 mL). The organic phase was extracted with dilute NaOH (0.5 M, 2 x 100 mL). The aqueous phase was extracted with ether (2 x 100 mL) and the combined organic phases were washed with water (100 mL), brine (100 mL) and dried (MgSO 4). The solvent was removed under reduced pressure to give 3-bromo-2,5,6-trifluorobenzoic acid (17.25 g, 84.5%) as white microcrystalline needles, m.p. was 114-116 ° C (sublimed).

46 94750

Example KK

1-Bromo-2,4,5-trifluoro-3- (trifluoromethyl) benzene 3-Bromo-2,5,6-trifluorobenzoic acid (16.92 g, 66 mmol) was heated under SF 4 (60 g) and HF (30 g). g) with a stainless steel bomb at 120 ° C for 8 hours. After the reaction mixture was cooled to 25 ° C, the volatiles were removed through KOH locks, and when gas evolution ceased, the vessel was extracted with CH 2 Cl 2 (150 mL). This solution was washed with dilute NaHCO 3 solution (sat. / 2, 50 mL), brine (50 mL) and dried (MgSO 4). The solvent was removed by distillation through a 15 cm Vigreux column, and the residue was distilled under a nitrogen atmosphere through a short distillation column at 147-150 ° C to give 1-bromo-2,4,5-trifluoro-3- (trifluoromethyl) benzene (15, 79 g, 83%) as a pale yellow oil.

NMR (CDCl 3): 67.67 (1H, t of d, Jd = 6 Hz, Jt = 8.1 Hz, aromatic).

Example LL

2,4,5-Trifluoro-3- (trifluoromethyl) benzoic acid

A solution of n-butyllithium (2.6 M in hexane, 9.6 mL, 25 mmol) was added dropwise via addition funnel over 15 minutes to a solution of 1-bromo-2,4,5-trifluoro-3- (trifluoromethyl) benzene (7.00 g, 25 mmol) in ether (100 mL) and stirred under nitrogen at -78 ° C. After 5 minutes, the mixture was rapidly blown catheter into a suspension of dry ice (100 g) in ether (100 mL). After 5 minutes, TFA (2 mL) was added to this solution. After warming to 20 ° C, the solution was washed with dilute HCl (0.5 M, 20 mL) and extracted with dilute base (0.5 N, 2 x 50 mL). The combined basic extracts were washed with ether (25 mL), acidified with concentrated HCl (ca. 4 mL) and extracted with ether (3 x 50 mL). The combined ether extracts 4794750 were washed with water (50 ml), brine (50 ml) and dried (MgSO 4). The solvent was removed under reduced pressure to give 2,4,5-trifluoro-3- (trifluoromethyl) benzoic acid (4.21 g, 69%) as white microscopic needles, m.p. was 87-90 eC.

NMR (CDCl 3): 511.80 (1H, broad s, OH), 8.05 (1H, t d,

Jd = 6 Hz, J-j. * 9 Hz aromatic).

Example MM

N- (2-hydroxy-l.l-dimetvvlietvvlil-2.4.5-trifluoro-3- (trifluoromethyl) benzamide

A solution of 4.88 g (20.0 mmol) of 2,4,5-trifluoro-3- (trifluoromethyl) benzoic acid, 2.80 g (22.0 mmol) of oxalyl chloride and 50 ml of methylene chloride was treated with one drop DMF and stirred at room temperature for 4 hours. The solution was concentrated to a yellow oil which was dissolved in methylene chloride (20 mL) and added to a cold (ice bath) solution of 2.53 g (25 mmol) of triethylamine, 1.96 g (22 mmol) of 2-amino-2-methyl 1-propanol and 40 ml of methylene chloride. The mixture was allowed to slowly warm to room temperature overnight.

The solution was poured into 50 mL of 1 N HCl and the organic layer. separated and washed with water. The solution was dried over magnesium sulfate and concentrated to give 5.81 g of the title compound as a yellow oil.

Example NN

2- (2,4.5-trifluoro-3- (trifluoromethyl) PHENYL-4,4-di-methyl-2-oxazoline

A solution of 5.81 g (18.4 mmol) of N- (2-hydroxy-1,1-dimethylethyl) -2,4,5-trifluoro-3- (trifluoromethyl) benzamide in 100 ml of chloroform at 0 ° In C, was treated dropwise with 5 ml of thionyl chloride. The mixture was allowed to: warm to room temperature overnight. The solution was concentrated to a yellow oil which was dissolved in 20 mL of DMF and treated with 0.8 g (21.6 mmol) of 60% sodium hydride. This reaction mixture was stirred at room temperature for 18 hours, then poured into 50 mL of dilute NaHCO 3. The solution was extracted with ethyl acetate, the organic phase was washed with water and dried over magnesium sulfate. Concentration in vacuo gave an orange oil which was chromatographed on silica gel eluting with 2% methanol in chloroform to give 2.62 g of a yellow oil.

Example 00 2- (2,4,5-Trifluoro-3-trifluoromethyl) -6-methylphenyl-4,4,4-dimethyl-2-oxazoline

A solution of 1.12 g (11.0 mmol) of diisopropylamine in 5 mL of THF was cooled to 0 ° C under a nitrogen atmosphere and treated with 4.0 mL of 2.5 M n-butyllithium and stirred for 10 minutes. This lithium diisopropylamide solution was added dropwise to a solution of 2.36 g (8 mmol) of 2- [2,4,5-trifluoro-3- (trifluoromethyl) phenyl] -4,4-dimethyl-2-oxazoline. In 5 ml of THF at -78 ° C. The solution was stirred at -78 ° C for one hour, after which the reaction was quenched with 2.24 g (16 mmol) of methyl iodide. The mixture was allowed to slowly warm to room temperature, stirred for one hour and poured into 10 mL of 1 N HCl. This solution was extracted with ether and the extract was washed with water, dried over magnesium sulfate and concentrated to give 2.28 g of the title compound.

Example PP

3-Fexo-amino) -8-azabisylchlorof.2.2.11 octane dihydrochloride

A mixture of 4.6 g (20 mmol) of 8- (phenylmethyl) -8-azabicyclo [3.2.1] octan-3-one oxime [JRBagley and TNRiley, J. Heterocyclic Chem., 19, 485 (1982 )], 0.5 g of 49,94750 10% rhodium / carbon catalyst and 100 ml of acetic acid were hydrogenated until sufficient hydrogen was consumed. The reaction mixture was filtered and two equivalents of HCl were added. The solid was filtered to give 2.80 g of the title compound, m.p. was> 300 eC.

Example 00 3- (Endo-amino-8-azabicyclo [3.2.3] octane dihydrochloride

A solution of 7.33 g (25 mmol) of 3- (endo-amino) -8- (phenylmethyl) -8-azabicyclo [3.2.1] octane dihydrochloride [P.Dostert et al., Eur.J. Med.Chem.-Chim.Ther., 19, 105 (1984)], 1.0 g of 20% palladium / carbon catalyst and 100 methanol were hydrogenated until sufficient hydrogen was consumed. The reaction mixture was filtered and the filtrate was evaporated to give 4.5 g of the title compound which was used crude.

Example 1 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-5-methyl-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylic acid

A suspension of 0.85 g (2.85 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 1, 00 g (11.6 mmol) of anhydrous piperazine and 20 ml of acetonitrile were refluxed for 5 hours, followed by stirring at room temperature overnight. The precipitate was filtered, washed with water and acetonitrile and dried to give 0.91 g of the title compound, m.p. was 205-206 ° C.

50 94750

Example 2 7- (3-Amino-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid

A mixture of 1.00 g (3.36 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid was 0.63 g (3, 38 mmol) of 3- (tert-butoxycarbonyl) aminopyrrolidine, 1.00 g (9.91 mmol) of triethylamine and 35 ml of acetonitrile were refluxed for 5 hours, followed by stirring at room temperature overnight. The precipitate was filtered and washed with acetonitrile and ether. The crude product was suspended in 20 ml of 6 M hydrochloric acid and 20 ml of glacial acetic acid and heated at 60 ° C for 2 hours. The solution was concentrated to an oil which was triturated with isopropanol.

The solid was filtered and washed with ether to give 1.04 g of the title compound as the hydrochloride salt, m.p. was> 300 ° C.

Example 3 1-Cyclopropyl-7- [3- (ethylamino) methyl] -1-pyrrolidinyl-6,8-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid

A mixture of 0.80 g (2.70 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.41 g (3 , 20 mmol) of N-ethyl-3-pyrrolidinemethanamine, 0.82 g (8.10 mmol) of triethylamine and 25 ml of acetonitrile were refluxed for 4 hours, followed by stirring at room temperature overnight. The precipitate was filtered, washed with acetonitrile and ether and dried to give 0.90 g of the title compound, m.p. was 198-199 ° C.

51 94750

Example 4 7- [3- (Aminomethyl-3-methyl-1-pyrrolidinyl] -1-cyclopropyl-6,8-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid

A mixture of 0.60 g (2.02 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.28 g (2.45 mmol) of 3-methyl-3-pyrrolidinemethanamine, 0.61 g (6.06 mmol) of triethylamine and 20 ml of acetonitrile were refluxed for 4 hours, followed by stirring at room temperature overnight. The precipitate was filtered, washed with ether and dried to give 0.61 g of the title compound, m.p. was 182-184 ° C.

Example 5 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-5-methyl-7- [3-methyl-1-piperazinyl] -4-oxo-5-quinolinecarboxylic acid

A suspension of 0.80 g (2.69 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 1, 08 g (10.8 mmol) of 2-methylpiperazine and 20 ml of acetonitrile were boiled under reflux for 3 hours, then cooled in an ice bath. The precipitate was filtered, washed with water and acetonitrile and dried to give 0.76 g of the title compound, m.p. was 187-188 ° C.

Example 6 1-Cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylic acid

A suspension of 0.70 g (2.50 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.86 g (10.0 mmol) of anhydrous piper 5294750 racin and 20 ml of acetonitrile were refluxed for 5 hours, followed by stirring at room temperature overnight. The precipitate was filtered, washed with water and acetonitrile and dried to give 0.85 g of the title compound, m.p. was 226-228 eC.

Example 7 1-Cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-7- (3-methyl-11-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid

A mixture of 0.75 g (2.68 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 1.07 g (10.4 mmol) mmol) of 2-methylpiperazine and 30 ml of acetonitrile were refluxed for 5 hours, then stirred at room temperature overnight. The precipitate was filtered, washed with water / ethanol and acetonitrile and dried to give 0.42 g of the title compound, m.p. was 189-192 ° C.

Example 8 7- (3-Amino-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid A mixture of 0.70 g (2 , 50 mmol) 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.56 g (3.00 mmol) of 3- (tert-butoxycarboxylic acid). carbonyl) aminopyrrolidine, 0.76 g (7.52 mmol) of triethylamine and 25 ml of acetonitrile were refluxed for 4.5 hours, then stirred at room temperature overnight. The solids were filtered and washed with acetonitrile and ether. The crude product was dissolved in 20 any 6 N hydrochloric acid and 20 any acetic acid and stirred at room temperature for 3 hours. The solution was concentrated to an oil which was triturated with a 2tl mixture of ether and isopropanol. The solids were filtered and washed with ether to give 0.95 g of the title compound as the hydrochloride salt, m.p. was> 300 ec.

Example 9 7- [3- (Aminomethyl) -3-methyl-1-pyrrolidinyl] -1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid

A mixture of 0.61 g (2.18 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.56 g (2 , 61 mmol) of 3 - [(tert-butoxycarbonyl) aminomethyl] -3-methylpyrrolidine, 0.66 g (6.54 mmol) of triethylamine and 25 ml of acetonitrile, was refluxed for 6 hours, then stirred at room temperature overnight. . The precipitate was filtered and washed with acetonitrile and ether. The crude product was suspended in 20 ml of 6 N hydrochloric acid and 20 ml of glacial acetic acid and stirred at room temperature for 3 hours.

The solution was concentrated and the residue was triturated with ether. The solid was filtered and washed with ether to give 0.61 g of the title compound as the hydrochloride, m.p. was 250-252 ° C.

«#«

Example 10 8-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-7- [1-piperazinyl] -3-quinolinecarboxylic acid

A suspension of 0.38 g (1.21 mmol) of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.42 g (4.88 mmol) piperazine and 20 mL acetonitrile were refluxed for 4 hours, then stirred at room temperature overnight. The precipitate was filtered and washed with water and acetonitrile to give 0.32 g of the title compound: m.p. was 234-235 ° C.

54 94750

Example 11 7- (3-Amino-1-pyrrolidinyl) -8-chloro-1-chloropropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid

A mixture of 0.50 g (1.60 mmol) of 8-chloro-1-cyclopropyl-6/7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.36 g (1.93 mmol) of 3- (tert-butoxycarbonyl) aminopyrrolidine, 0.48 g (4.75 mmol) of triethylamine and 20 ml of acetonitrile were refluxed under cooling for 4 hours, followed by stirring at room temperature overnight. over. The solution was concentrated and the residue was triturated with a 1: 1 mixture of ether and hexane and filtered. The solid was washed with water and hexane. The crude product was suspended in 15 ml of dichloromethane and 1.5 ml of trifluoroacetic acid and stirred at room temperature for 4 hours. The solution was concentrated to a golden solid which was suspended in water, basified (pH 11) with 10% sodium hydroxide and filtered. The solution was then neutralized (pH 7.10) and the precipitate was filtered and washed with water to give 0.29 g of the title compound, m.p. was 124-126 ° C.

«4

Example 12 1-Ethyl-6,8-difluoro-1,4-dihydro-5-methyl-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylic acid

A mixture of 0.45 g (1.58 mmol) of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.54 g (6.27 mmol) of anhydrous piperazine and 20 ml of acetonitrile were refluxed for 3 hours, then cooled to room temperature.

The solids were filtered and washed with water, acetonitrile and ether to give 0.48 g of the title compound, m.p. was 223-225 ° C.

55 94750

Example 13 7- (3-Amino-1-pyrrolidinyl) -1-ethyl-6,8-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid

A mixture of 0.36 g (1.25 mmol) of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.26 g (1.39 mmol) of 3- (tert-butoxycarbonyl) aminopyrrolidine, 0.38 g (3.76 mmol) of triethylamine and 20 ml of acetonitrile were refluxed for 5 hours, followed by stirring at room temperature overnight. The solids were filtered and washed with acetonitrile and ether. The crude product was dissolved in 5 ml of 6 N hydrochloric acid and 5 ml of glacial acetic acid and stirred for 5 hours at room temperature. The solution was concentrated to a solid which was suspended in water, basified (pH 12), filtered through a pad of glass fiber and neutralized (pH 6.8). The solids were filtered and washed with water to give 0.32 g of a white solid, m.p. was 218-220 ° C.

Example 14 6,8-Difluoro-1- (2,4-difluorophenyl) -1,4-dihydro-5-methyl-4-oxo-7-f-piperazinyl) -3-quinolinecarboxylic acid

A solution of 0.43 g (1.08 mmol) of ethyl 6,7,8-trifluoro-1- (2,4-difluorophenyl) -1,4-dihydro-5-methyl-4-oxo- 3-Quinolinecarboxylic acid, 0.37 g (4.30 mmol) of anhydrous piperazine and 20 mL of acetonitrile were refluxed overnight, cooled to room temperature and concentrated. The residue was taken up in 10 ml of 6 N hydrochloric acid and refluxed for 2 hours. The mixture was cooled and the solids were filtered. The crude product was suspended in water, basified (pH 12), filtered through a pad of glass fiber and neutralized (pH 6.5). The solids were filtered and washed with water and ether to give 0.37 g of the title compound, m.p. was 283-284 ° C.

56 94750

The following compound was prepared by the same method: a) 6,8-Difluoro-1- (2,4-difluorophenyl) -1,4-dihydro-5-methyl-7- (3,5-dimethyl-1-piperazinyl) -4-oxo-3-quino -liinikarboksvvlihappo. mp 240-242 ° C.

Example 15 7- (3-Amino-1-pyrrolidinyl) -6,8-difluoro-1- (2,4-difluoro-phenyl) -1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid

A solution of 0.40 g (1.00 mmol) of ethyl 6,7,8-trifluoro-1- (2,4-difluorophenyl) -1,4-dihydro-5-methyl-4-oxo- 3-Quinolinecarboxylic acid, 0.22 g (1.18 mmol) of 3- (tert-butoxycarbonyl) aminopyrrolidine, 0.30 g (3.00 mmol) of triethylamine and 15 ml of acetonitrile were refluxed for 18 hours. The mixture was cooled and concentrated. The residue was dissolved in 10 ml of 6 N hydrochloric acid, refluxed for 3 hours and cooled to room temperature. The solids were filtered, washed with water and ether and suspended in water. The suspension was basified (pH 12) and filtered through a pad of glass fiber and the filtrate was neutralized to pH 6.7. The solids were filtered and washed. with water and ether gave 0.38 g of the title compound, m.p. was 230-232 ° C.

Example 16 6,8-Difluoro-1,4-dihydro-5-methyl-4-oxo-7- (1-piperazinyl) -1-vinyl-3-quinolinecarboxylic acid

A solution of 0.69 g (1.80 mmol) of ethyl 6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-1-vinyl-3-quinolinecarboxylate, 0.62 g (7.2 mmol) of anhydrous piperazine and 20 ml of acetonitrile were refluxed for 18 hours, cooled and concentrated. The residue was suspended in 25 ml of 1 N sodium hydroxide and heated at 80 ° C for 90 minutes. The clear, yellow solution was cooled to room temperature, filtered and neutralized (pH 6.8) with 6 N hydrochloric acid. The solids were filtered, washed with water and ether and dried to give 0.32 g of the title compound, m.p. It was 222-225 ° C.

The following compound was prepared in a similar manner: a) 6,8-Difluoro-1,4-dihydro-5-methyl-7- (3-methyl-1-oiprazinyl) -1-vinyl-3-quinolinecarboxylic acid. mp

232-235 ° C.

Example 17

6-Fluoro-1- (2,4-difluorophenyl-1,4-dihydro-5-methyl-4-oxo-7-fluoroacinyl) -3-quinolinecarboxylic acid PDQ

A solution of 0.76 g (2.00 mmol) of ethyl 6,7-difluoro-1- (2,4-difluorophenyl) -1,4-dihydro-5-methyl-4-oxo-3- quinolinecarboxylate, 0.69 g (8.00 mmol) of anhydrous piperazine and 30 mL of acetonitrile were refluxed for 18 hours, cooled and concentrated. The residue was dissolved in 20 ml of 6 N hydrochloric acid and refluxed for 3 hours. Suspension: cooled, concentrated to half volume and filtered and the solids washed with water. The crude product was suspended in water, basified (pH 12), filtered and neutralized to pH 6.8. The precipitate was filtered, washed with water and dried to give 0.58 g of the title compound, m.p. was 198-200 ° C.

The following compounds were prepared using essentially the same procedure: a) 6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-5-methyl-7- (3-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylate. svvlihappo. mp 188-191 ° C; 58 94750 b) 6-Fluoro-1- (2,4-difluorophenyl-1,4-dihydro-5-methyl-7- (3,5-dimethyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid. 213-215 DEG C. c) 7- [3-Amino-1-pyrrolidinyl] -6-fluoro-1- (2,4-difluoro-phenyl-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid). mp 232-234 DEG C. d) 7- [3- (Ethylamino] ethyl] -1-pyrrolidinyl-6-fluoro-1- (2,4-difluorophenyl-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid mp 196-198 ° C and e) 7- [3- (aminomethyl-3-methyl-1-pyrrolidinyl] -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-5-methyl- 4-Oxo-3-quinolinecarboxylic acid, mp 181-184 ° C.

Example 18 7- (3-Amino-1-pyrrolidinyl-1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid

Triethylamine (0.17 mL, 1.2 mmol), 3- (1,1-dimethylethoxycarbonylamino) pyrrolidine (0.22 g, 2.1 mmol) and 0.39 g (1.2 mmol) of 7- Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester was dissolved in acetonitrile (10 ml). and the mixture was heated at reflux for 4 hours, then cooled and diluted with ether (50 mL). This solution was washed with saturated KHCO 3 and NaCl solutions and dried over Na 2 SO 4. and evaporated, after which the product obtained was dissolved in ether and allowed to stand, the crystals formed were collected, 0.56 g of intermediate ester were obtained, the intermediate ester was dissolved in acetic acid (15 ml) and 6N HCl (1 ml) was added and the mixture was heated. refluxing under cooling for 2 hours, after which it was evaporated to a gum, which was dissolved in ethanol (10 ml) and 5N NaOH (2 ml) was added and the mixture was stirred for 2 hours.

59 94750

The reaction mixture was evaporated to a gum and dissolved in water (60 ml) to give a solution having a pH of 12. The pH was adjusted to 6.5 and the resulting solid was collected and washed with water and dried to give the title compound (0.38 g).

Example 19 1-Cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-7- (1-piperazinyl-8,8-naphthyridine-3-carboxylic acid The procedure of Example 18 was used to prepare the title compound 58%: n yield.

Example 20 1-Ethyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo- (1-piperazinyl) -3-quinolinecarboxylic acid

A suspension of 0.67 g (2.50 mmol) of 1-ethyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.86 g ( 10.0 mmol) of anhydrous piperazine and 25 ml of acetonitrile were refluxed for 6 hours, then cooled to room temperature. The solids were filtered, washed with water and ether and dried to give 0.58 g of the title compound, m.p. was 225-227 ° C.

The following compounds were prepared using essentially the same method: a) 1-Ethyl-7- [3- (ethylamino) methyl] -1-pyrrolidinyl] -6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid. mp 180-182 ° C; b) 7- (3- (Amino-1-pyrrolidinyl) -1-ethyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid. mp 210-213 ° C; c) 1-ethyl-6-fluoro-1,4-dihydro-5-methyl-7- (3-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid.

60 94750 SUl.p. 228-231 ° C; d) 1-ethyl-6-fluoro-1. 4-Dihydro-5-methyl-7- (3,5-dimethyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid. mp 219-221 ° C; e) 7- [3- (Aminoethyl) -3-methyl-1-pyrrolidinyl] -1-ethyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid. mp 223-225 ° C.

Example 21 7- [3- (Endo-amino) -8-azabis-chloro-3,2.11-oct-8-yl-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo- 3-quinolinecarboxylic acid

A mixture of 0.50 g (1.6 mmol) of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.36 g (1.8 mmol) of 3- (endo-amino) -8-azabicyclo [3.2.1] octane dihydrochloride, 0.72 ml (4.8 mmol) of 1,8-diazabicyclo [5.4.0] undec-7-ene and 15 ml of acetonitrile, was refluxed for 18 hours. The suspension was cooled to room temperature, diluted with ether and cooled. The resulting solid was filtered, washed with ethanol and ether and dried to give the title compound.

•

The following compounds were prepared in a similar manner:

Example a: 7- [3- (Endo-amino) -8-azabicyclo [3.2.1] oct-8-yl] -6,8-difluoro-1- (2,4-difluorophenyl) -1,4-dihydro -5-methyl-4-oxo-3-quinolinecarboxylic acid.

Example b: 7- [3- (endo-amino) -8-azabicyclo [3.2.1] oct-8-yl] -1-cyclopropyl-6,8-difluoro-1,4-dihydro-5-methyl- ♦ 4-Oxo-3-quinolinecarboxylic acid.

Il

Claims (1)

94750 Claim A process for the preparation of compounds of the formula R F ^ Jv ^ COOH, 9. H wherein R is alkyl, characterized in that (a) a compound of formula Λ is reacted with a base and trimethylsilyl chloride to give a compound of formula t Λ SiMe3 (b) this compound is reacted with a base and an alkyl halide to produce a compound, of formula, jj3 SiMe3 (c) The SiMe3 group is removed and • (d) the formed compound is hydrolyzed. 94750 For the preparation of the formulation with the formulation RF ^ L, COOH H color R is alkyl, the resultant is that (a) the formulation with the base and trimethylsilyl chloride for the formulation with the formulation, Λ> Si (b) the composition of the base and the alkyl halide for the production of the formula. i # SiMe3 (c) The SiMej Group has the following characteristics: (d) the image of hydrolysers.