CA1333715C

CA1333715C - Process for the preparation of quinolonecarboxylic acids

Info

Publication number: CA1333715C
Application number: CA000572825A
Authority: CA
Inventors: Rudolf Zerbes; Michael Preiss
Original assignee: Bayer AG
Current assignee: Bayer Pharma AG
Priority date: 1987-07-24
Filing date: 1988-07-22
Publication date: 1994-12-27
Anticipated expiration: 2011-12-27
Also published as: AU602226B2; PT88078A; JPS6440460A; NO174773B; DK412488A; AU1902488A; KR890002020A; ZA885332B; IE882255L; EP0300311A3; CN1030911A; EP0300311B1; FI883452A7; EP0300311A2; IL87185A0; HU205082B; UA8018A1; ATE111898T1; PT88078B; ES2058186T3

Abstract

A one pot process comprising the following reactions:

+ (II) (III) (IV) (V)

Description

The invention relates to a new process for the preparation of 4-oxo-3-quinoline-carboxylic acids which are used as intermediates for the preparation of known quinolonecarboxylic acids having pharmaceutical activity.
It is known that 1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acids are ob-tained in the following way:
1st stage:

F~ eH_ COOR ~ ~ ~ ,COOR

Cl CH-N(CH3)2 ll Cl Cl Cl CH-N(CH3)2 (1) (2) ~3) 2nd stage:

( 3 ) ~ D~H2 F~C COOR

- ~CH3 )2NH Cl Cl CH-NH--<¦

3rd stage:

( 5 ) ~ K2C3 ~COOR

Cl J~

~6) Le A 25 272 4th stage:

(6) hydrolysis F~COOH
Cl ~\
~7) It has also been disclosed to prepare (7) in the follo~ing way:
1st stage:

C ~ COzR C ~ ;CH~CO2R)2 2nd stage:

decarboxylation ~ C~ ,~02R
~ CH2 Cl Cl 3rd stage:

~C02R
CH(OEt.)3 ' J.~ IC
C 1 C 1 CH- Oc2H5 4th stage:

D--NH2 , ~C~ ~C02R
C I CH-NH--<]

Le A 25 272 5th stage:

K2C3 C~f 02R

6th stage:

hydrolysis ~ OOH

CI

S However, all the known processes have the disad-vantage that the target compound is prepared via many intermediate stages.
Moreover, elaborate separation and drying opera-tions must be carried out.
The washing procedures which become necessary thereby mean that large amounts of solvents must be in-cinerated or reprocessed.
It is necessary to apply elaborate analytical meth-ods for the characterization of the intermediate stages.
The invention relates to a process for the pre-paration of quinolonecarboxylic acids of the general for-mula I

X~OOH ( I ) R

in ~hich Z0 R1 represents propyl, cyclopropyl, isopropyl Le A 25 272 133371~
or vinyl, x1 denotes fluorine, chlorine, Br, CN, N02 or hydrogen, and X2, X3 and X4 represent fluorine, chlorine, N02 S or hydrogen, which is characterized in that a compound of the formula II

X~OCl (II) in which x1 to X4 have the abovementioned meaning, and XS represents halogen, in particular chlorine or fluorine, is reacted, without isolation of intermediate stages in a so-called one-pot reaction, with a compound of the for-mula (III) IlH-cooR2 CH-tJR3R3 (III) in which R2 and R3 are identical or different and rep-resent C1-C4-alkyl, in the presence of a solvent and of a base, where approp-riate heating to SûC to 150C, to give the compounds of the formula IV
X~ O O
1 li 11 X3~:-C-C-OR2 ( I V ) X

Le A 25 272 133371~
these compounds IV are subjected to an amine exchange at temperatures of 50C to 120C in the presence of the abovementioned solvents and in the presence of an amine of the formula R1NH2 in which R1 has the abovementioned meaning, resulting in the compounds of the formula X~C_C_oR2 ( V ) X2 Xl CH-NH-Rl having the abovementioned radical meanings, and sub-sequently the compounds V are cyclized and hydrolysed at temperatures between 80C and 180C in the presence of a base, and the compounds of the formula I are precipitated by addition of acid.
The compounds which are prepared according to the invention, in particular, are those in which R1 in formula I represents a cyclopropyl radical. 5 Preferably: X1 and X4 = hydrogen, x2 = chlorine and X3 = fluorine.
Additionally preferred compounds of the formula I are those in which R1 denotes cyclopropyl, x2 repre-sents chlorine, and X1 and X3 denote fluorine, while X4 represents hydrogen.
Compounds which are furthermore preferred are those in which X3 represents fluorine, and X1 and x2 represent chlorine, while X4 denotes hydrogen.
Given the complicated course of the reaction, it has to be designated extremely surprising that the com-pound 1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid can be prepared without iso-lation of intermediates in a "one-pot" reaction in excel-lent yields by the following route:

Le A 25 272 a) acylation C ~ OCl CH-COOR2 tert. org. BASE~ ~COOR2 inert org. solvent l CH-NR3R3 Suitable org. solvents are:
toluene, xylene, cyclohexane, open-chain hydrocarbons (mixtures), DMF, and DMS0.
Bases which can be used are:
tert. org. amines such as R3N with R = C1-C4-alkyl, benzyl, cycl. amines R-N N-R

r--~ R
O~__~N-R

pyridine, etc., with R = C1-C4-alkyl.
The temperatures for the acylation of the dimethyl-am;noacrylic ester are between 50C and 150C, preferably at 80C to 120C.
Hydrochloride, which precipitates out during the reaction, of the auxiliary base can be separated out via a filter or be removed by extraction by stirring with water.
The org. phase with the aroylacrylic ester is fur-ther reacted with cyclopropylamine.
Le A 25 272 This reaction can be carried out in the same sol-vent or, after evaporation (in vacuo or under atmospheric pressure), in another solvent.
b)amine exchange:

1l~ ~COOR2 C ~ ll ¦>~H2 Cl CH-N(CH3 )2 1l ~ C~ ~COOR

C ~ Cl CH-N
Suitable solvents are:
toluene, xylene, cyclohexane, open-chain hydrocarbons (mixtures), alcohols, DMF, DMS0 and butylglycol.
The temperatures for the amine exchange are at 50C to 120C, preferably at 65C to 85C.
The reaction mixture is maintained further at the elevated temperature until the evolution of gas (dimethyl-amine) ceases.
If the amine exchange is carried out in a low-boiling diluent such as, for example, cyclohexane, the solvent is evaporated off before the cyclization (in vacuo or under atmospheric pressure) and replaced by a higher-boiling diluent such as, for example, butylglycol.

Le A 25 272 133~71S
c) cyclization:

F~C~ ~COOR

C~ CH Nl~a o ~ OOR

Suitable solvents are:
higher alcohols such as butylglycol i-propyl alcohol, ethylene glycol butanol, triethylene glycol, polyethylene glycol, amino alcohols such as diethylaminoethanol, DMF, DMS0, dioxane and N-methylpyrrolidone.
The cyclization to give the quinolone system is carried out at temperatures bet~een 80C and 180C, pre-ferably at 130C to 160C, in the presence of a base.
~ases which can be used are:
Na tert.-butylate, NaH and K2C03 .
The base is used in an equimolar amount or up to an excess of 3 ~ole-equ;valents, preferably in an excess of 0.1 to 0.5 mole-equivalents.

Le A 25 272 133371~i d) hydrolysis and precipitation O . O
2R ~OOH

For the hydrolysis, the reaction mixture is cooled to about 100C, and water is added.
Owing to the excess of base in the cyclization, the hydrolysis is complete within a short time at tempera-tures of 50C to 100C.
The quinolone carboxylic acid is precipitated by ad-dition of a mineral acid or an org. acid and is isolated.
Suitable and preferred acids are:
sulphuric acid, hydrochloric acid and acetic acid.
Example 1 28.8 9 of ethyl N,N-dimethylamino-acrylate and 26 9 of N,N-dimethylbenzylamine in 71 ml of toluene are heated to 90C and, at this temperature, 40 9 of 2,4-di-chloro-5-fluorobenzoyl chloride are added dropwise in 60 min.
The mixture is then stirred for 15 min, and the precipitated N,N-dimethylbenzylamine hydrochloride is separated off through a suction filter funnel.
The filtrate is substantially evaporated in vacuo, and 80 ml of butylglycol are added to the residue.
13 9 of cyclopropylam;ne are added dropwise at 70-75C in 30 min and, after addition is complete, the mixture is maintained at 100C for 1 hour until the evo-lution of gas ceases.
27.9 9 of potassium carbonate and 100 ml of butyl-glycol are added to the reaction mixture, which is thenLe A 25 272 slowly heated to 135-145C.
During this, about 40 ml of low-boiling constitu-ents distil out.
The temperature is maintained for 1.5 h.
It is then cooled to 100-120C, and 130 ml of water are added to the reaction mixture.
The mixture is stirred at 90C for 15 min and, at this temperature, 27 ml of acetic acid are added drop-wise in 15 min. The contents of the flask are cooled, and the solid is separated off through a suction filter funnel.
The product is washed with 27 ml of water and 5û ml of methanol, sucked thoroughly dry and dried at 70C in vacuo for 24 h.
Yield: 37 9 = 74.9% of theory.
Example 2 43.2 9 of ethyl N,N-dimethylamino-acrylate in 84 mL of toluene are heated to 100C, and 40 ml of tri-ethylamine are added.
At the reflux temperature, 60 9 of 2,4-dichloro-5-fluorobenzoyl chloride are added dropwise in 30 min, and then the precipitated triethylamine hydrochloride is separated off through a suction filter funnel.
After washing with 65 ml of toluene, 16.2 9 of cyclopropylamine are added dropwise to the filtrate at 70C in Z0 min.
The mixture is heated at 100C until evolution of gas ceases.
Then 42 9 of potassium carbonate and 270 ml of butylglycol are added, and the mixture is slowly heated to 135-145C. During this, about 180 ml of toluene and low-boiling constituents distil out.
135-145C are maintained for 1.5 h and, after the reaction mixture has been cooled to 100C, 200 ml of water are added.
After 15 min, 40.5 ml of acetic acid are added Le A 25 272 dropwise at 90C, and the precipitated solid is fil-tered off with suction through a suction filter funnel.
The product is then washed with 140 ml of water and 75 ml of methanol, thoroughly sucked dry and dried S at 70C in vacuo for 24 h.
Yield: 58.5 9 = 79X of theory.
Example 3 44.7 9 of ethyl N,N-dimethylaminoacrylate and 17.1 9 of N,N~-dimethylpiperazine in 95 ml of cyclohexane are heated to reflux.
62 9 of 2,4-dichloro-5-fluoro-benzoyl chloride are added dropwise in 1 h.
The precipitated dimethylbenzylamine hydrochloride is separated off through a suction filter funnel, and the filtrate is evaporated to dryness in vacuo.
The residue is dissolved in 125 ml of butylglycol and, at 90C, 20.2 9 of cyclopropylamine are added drop-wise to the solution.
After the evolution of gas ceases, 43.4 9 of pot-Z0 assium carbonate and 165 ml of butylglycol are added, andthe mixture is heated at 145C for 1.5 h. Initially during this small amounts of low-boiling constituents dis-til out.
After 1.5 h, the mixture is cooled to 100C, 205 ml of water are added, and the mixture is then stirred at 95C for 15 min.
Then 42 9 of acetic acid are added dropwise in 15 min, the temperature is reduced to 30C, and the pre-cipitated solid is separated off on a suction filter fun-nel.
The filter cake is washed with 180 ml of waterand 80 ml of 80~ strength ;sopropanol and is dried at 70C
in vacuo overnight.
Yield: 60.1 9 = 78.1Z of theory.
Example 4 33.7 9 of methyl N,N-dimethylamino-acrylate are Le A 25 272 heated with 40 5 9 of N,N-dimethylbenzylamine in 95 ml of toluene at 110C.
At the reflux temperature, 62 9 of 2,4-dichloro-5-fluorobenzoyl chloride are added dropwise in 1 h, and then S the precipitated dimethylbenzylamine hydrochloride is re-moved through a suction filter funnel.
The solvent is distilled off in vacuo, 130 ml of butylglycol are added and, at 90C, 20.2 9 of cyclopropyl-amine are added dropwise in 20 min.
After the evolution of gas ceases, 43.4 9 of potassium carbonate and 150 ml of butylglycol are added to the reaction mixture which is then slowly heated to 140C. During this, small amounts of low-boiling solvent distil out.
The mixture is then stirred at 140C for 1.5 h.
After cooling to 100C, 205 ml of water are added to the reaction mixture and it is then stirred at 90C for 15 min.
While cooling slightly, 100 ml of 30% strength sulphuric acid are added, and the solid is filtered off with suction on a suction filter funnel and is washed with 200 ml of uater and 200 ml of isopropanol.
The solid is dried in vacuo at 70C overnight.
Yield: 59.4 9 = 77.2X of theory.
Example 5 55.6 9 of tributylamine are added to 44.7 9 of ethyl N,N-dimethylamino-acrylate in 95 ml of cyclohexane and, at 85-95C, 62 9 of 2,4-dichloro-5-fluorobenzoyl chloride are added dropwise in 1 h.
Then 250 ml of water are added to the reaction mixture, and the aqueous salt phase is separated off.
The aqueous phase is extracted 1 x more by stir-ring with 50 ml of cyclohexane, and the combined org.
phases are evaporated to dryness under water pump vacuum.
The residue is taken up in 125 ml of butylglycol, and the mixture is heated to 70C and 20.2 9 of Le A 25 272 cyclopropylamine are added dropwise in 15 min.
After the evolution of gas ceases, a further 160 ml of butylglycol and 44 9 of potassium carbonate are added, and the mixture is slowly heated to 140C.
After the mixture has reached 140C, it is stirred for 1.5 h and then cooled to 100C, and 205 ml of water are added.
After 15 min, 42 9 of acetic acid are added drop-wise in 10 min, and the mixture is cooled to room tempera-ture.
The precipitate is isolated through a suction fil-ter funnel and is washed ~ith water and isopropanol.
The yield obtained after drying at 50C in vacuo overnight is 54.6 9 = 71% of theory.
Example 6 105 9 of tributylamine and 86 9 of methyl N,N-dimethylamino-acrylate in 148 ml of toluene are heated to 105C, and 124 9 of 2,4-dichloro-S-fluoro-benzoyl chlor-ide are added dropwise in 1 h.
After the reaction mixture has been cooled to 50C, it is extracted 2 x with 250 ml of water each time.
The organic phase is substantially concentrated under water pump vacuum, and 37.5 9 of cyclopropylamine are added dropwise to the residue at an internal tempera-ture of 70-75C. This results in gaseous dimethylamine escaping until the reaction is complete.
86.8 9 of potassium carbonate and 500 ml of butyl-glycol are added to the reaction mixture which is then slowly heated to 135 - 145C. During this, small amounts of low-boiling solvents distil out.
135 - 145C are maintained for 1.5 h, and then the mixture is cooled to 100C, and 535 ml of a 10% strength acetic acid are added dropwise.
The resulting suspension is cooled to room tem-perature, and the sol;d is separated off through a suctionfilter funnel and washed with 175 ml of water and 200 ml Le A 25 272 of 80X strength isopropanol.
The product is dried in vacuo at 70C overnight.
Yield: 220 9 = 78.1% of theory.

Le A 25 272

Claims

1. A process for the preparation of a quinolonecarboxy-lic acid of the general formula I:

(I) in which R1 represents propyl, cyclopropyl, isopropyl or vinyl, X1 denotes fluorine, chlorine, Br, CN, NO2 or hydrogen, and X2, X3 and X4 represent fluorine, chlorine, NO2 or hydrogen, which process comprises reacting a compound of the formula II:

(II) in which X1 to X4 have the abovementioned meanings, and X5 represents halogen, with a compound of the formula III:

(III) in which R2 and R3 are identical or different and represent C1-C4 alkyl, in the presence of a solvent and of a base, to obtain a compound of the Formula IV:

(IV) subjecting the compound of formula IV to an amine exchange at a temperature of 50°C to 120°C in the presence of a solvent and in the presence of an amine of the formula R1NH2 in which R1 has the abovementioned meaning, to obtain a compound of the formula (V) in which X, X2, X3, X4, X5, R1 and R2 are as defined above subsequent-ly cyclizing and hydrolyzing the compound of formula V at a temperature between 80°C and 180°C in the presence of a base, and precipitating the compound of the formula I by addition of acid, wherein the process is carried out without isolation of inter-mediate compounds.

2. A process according to claim 1, wherein the reaction to obtain the compound of formula I is carried out without isolation of the product of intermediate stages, in a one-pot reaction.

3. A process according to claim 1, wherein X5 represents chlorine or fluorine.

4. A process according to claim 1, wherein during the reaction of the compound of formula II with the compound of formula III the reactants are heated to a temperature in the range 50°C to 150°C.

5. A process according to claim 1, 2 or 3, wherein R1 represents cyclopropyl.

6. A process according to claim 1, 2 or 3, wherein R1 represents cyclopropyl, X1, X2 and X3 are identical or different and represent fluorine or chlorine and X4 represents hydrogen.

7. A process according to claim 1, 2 or 3, wherein R1 represents cyclopropyl, X1 and X4 represent hydrogen, X3 represents fluorine and X2 represents chlorine.

8. A process according to claim 1, 2 or 3, wherein R1 represents cyclopropyl, X1 and X2 represent chlorine, X3 represents fluorine and X4 represents hydrogen.

9. A process for preparing 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid which comprises reacting ethyl N,N-dimethylamino-acrylate or methyl N,N-dimethylamino-acrylate with 2,4-dichloro-5-fluorobenzoyl chloride in a solvent and in the presence of a base, subjecting the product obtained to an amine exchange reaction with cyclopropylamine at a temperature of 50°C to 120°C in a solvent, cyclizing the product of the amine exchange by reaction with a base at 80°C to 180°C, hydrolysing and precipitating the required 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid by addition of acid, wherein the process is carried out without isolation of intermediate compounds.