DK174855B1 - Process for the preparation of guinolone carboxylic acids - Google Patents

Description

in DK 174855 B1

The present invention relates to a particular process for the preparation of 4-oxo-3-quinoline carboxylic acids which finds use as intermediates for the preparation of known pharmaceutically active quinolone carboxylic acids.

It is known (EP-A-004 279) that certain enamines can be reacted with certain o-halo-heteroaryl-carboxylic acid halides in two reaction steps, each time in the presence of a base, without particular isolation of the intermediate to form of corresponding 4-oxo-1,8-naphthyridine-3-carboxylic acid derivatives, and that the resulting isolated carboxylic acid derivative can then be converted to the corresponding carboxylic acid.

It is further known (EP-A-176 846) that 1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acids is obtained as follows Step 1:

ISLAND

II

F »C0C1 F. c COOR

CH-COOR - ν '20 JLJL + ιί Bae® xx s CH-K (CHa) 2 li

Cl Cl 32 Cl Cl CH-N (CH3> (1) (2) (3) Step 2: 25

ISLAND

II

. . C COOR

«3» * t> -NH2 - XXT

30,, - (CH3) 2NH Cl C1 CH-NH- <] (4) (5) ^ 2 DK 174855 B1 Step 3:. - · - - 'χώτ

“A

(6) 4th Step: 10 o

saponification

...- XXX

“A

15 <7)

It is also known (EP-A-078 362) to prepare the compound (7) as follows: Step 1:

ISLAND

-VY ™. ^ U £ _ XC "·" "· 25 2nd Step: 0

30 Pe ^ rboxvterlpq, ^ COjB

ΛΛ CH2

Cl Cl 3 DK 174855 B1 3rd stage;

ISLAND

II

/ co2r. CH (0EI> 3 -> li 5 Cl Cl CH-OC2H5 4th step: 10 o - per

Cl Cl CH-NH 2 Vj Step 5:

ISLAND

4 K2C ° 3 -

C1 A

6th step; 25

ISLAND

F-Aggregation »II ^, .. u C1

However, the methods known from EP-A-176 846 and EP-A-078 362 all exhibit the disadvantage that the final compound is prepared over many intermediate steps.

In doing so, expensive separation and drying operations must be performed.

4 DK 174855 B1

During the necessary washing processes, large quantities of solvents must be incinerated or reprocessed.

A costly analysis is needed to characterize the intermediate stages.

The invention relates to a method of manufacture

of quinolone carboxylic acids of general formula I

3 π πΓ ΤΓ u> 10 Χ * * 1 «1 wherein 15 R 1 is propyl, cyclopropyl, isopropyl or vinyl,

X1 means fluorine, chlorine, Br, CN, NO2 or hydrogen, and X2, X3 and X4 mean fluorine, chlorine, NO2 or hydrogen, which is characterized by reacting a compound of the formula without an intermediate step in a so-called batch reaction. IX

Jt * 1 25

wherein X 1 to X 4 have the above meaning and X 1 represents halogen, especially chlorine or fluorine, with a compound of formula III

CH-COOR2 II,, III) CH-NR3R3

wherein R 2 and R 3 are the same or different and represent C 1 -C 4 alkyl, in the presence of a solvent and a base, optionally under heating to 50-150 ° C, to form a compound of formula IV

5 DK 174855 B1 JM Ϊ * 5 X0L ^ "" 'C3R3 tIV> s gHNR3R3 2 * j

this compound of formula IV undergoes an amine exchange 10 at temperatures of 50-120 ° C in the presence of the aforementioned solvents and in the presence of an amine of formula R-jrui * wherein R 1 has the above meaning to form a compound of formula V

x4 0 O.

15 I II II, * sYVic'tf

XI-NH-R, X2 in X® 20 having the above symbolic meanings, and then the compound of formula V rings at temperatures between 80 and 180 ° C in the presence of a base, saponifying and adding acid precipitates. compound of formula I.

In particular, according to the invention, such compounds are prepared in which R 1 of formula I represents a cyclopropyl group.

Preferably: X3 and X4 = hydrogen, X2 = chlorine, X3 = fluorine.

Also preferred are compounds of formula I wherein R 1 is cyclopropyl, X 2 is chlorine, and X 1 and X 3 are fluorine, while X 4 is hydrogen.

Further preferred are compounds in which X3 is fluorine and X1 and X2 are chlorine while X4 is hydrogen.

In the complicated course of the reaction, it should be noted that it is surprisingly surprising that the compound 1-cyclopropyl-7-5-chloro-6-fluoro-1,4-dihydro-4-oxo-3-guinoline carboxylic acid can be prepared without the intermediate step. a batch reaction in excellent yields as follows: a) Acylation 10 ch-coor2 II * II 3 3

ci ^ ci 'CH_NR R

o tiert. org. base_. ^ eoop2 15 indiff. org. solvent 'J | "ίΓ p C1 Cl CH-NR3R3 Speaking as organic solvents are: toluene, xylene, cyclohexane, open-chain hydrocarbons (mixtures), 20 DMF and DMSO.

As bases may be used: tertiary organic amines such as R 3 N with R = C 1 -C 4 alkyl, benzyl, cyclic amines r

25 I

R

_N ^ 0-R

pyridine, etc. with R = C 1 -C 4 alkyl.

The temperatures of the acylation of the dimethylaminoacrylic ester are between 50 and 150 ° C, preferably at 80-120 ° C.

During the reaction, precipitated hydrochloride of the auxiliary base can be separated through a filter or removed by stirring with water.

The organic phase with the aroyl acrylic ester is further reacted with cyclopropylamine.

Thereby, the reaction can take place in the same solvent or after evaporation (in vacuo or under normal pressure) in another solvent.

b) Amine exchange: 0 5 ^ II 2

FSX ^^ C \ x ^ COOR - (CH3) 2HH

XX § -

Cl Cl cH-N (CHo) 2 o

10 'YCV'C / C00R

Cl Cl ch-NH- ^

Solvents may be used: toluene, xylene, cyclohexane, open-chain hydrocarbons (mixtures), 15 alcohols, DMF, DMSO and butyl glycol.

The temperatures of the amine exchange are at 50-120 ° C, preferably at 65-85 ° C.

The reaction mixture is kept at the elevated temperature until the gas evolution (dimethylamine) is completed.

If the amine exchange is carried out in a low boiling diluent, e.g. cyclohexane, the solvent is evaporated prior to the cyclization (in vacuum or at normal pressure) and replaced by a higher boiling diluent, e.g. butyl glycol.

C) Closure: 0 * K 2 CO 3

30 Cl Cl cH tubes <3 I

- x & ~

"A

Speaking as solvents come higher alcohols such as isopropyl alcohol, butanol, butyl glycol, ethylene glycol, triethylene glycol, polyethylene glycol, amino alcohols such as diethylaminoethanol, DMF, DMSO, dioxane and N - methyl pyrrolidone. The cycling of the quinolone system occurs at temperatures between 80 and 180 ° C, preferably at 130-160 ° C in the presence of a base.

As bases may be used: Na-tert-bututylate, NaH and KgCO3.

The base is used from equimolar to an excess of 3 molar equivalents, preferably in an excess of 0.1-0.5 molar equivalents.

d) Saponification and precipitation: χότ · '- 20ir "" A, ^ 20

For saponification, the reaction mixture is cooled to ca. 100 ° C, then water is added.

Due to the excess base at the ring closure 25, the saponification at temperatures of 50-100 ° C is completed in a short time.

The quinolone carboxylic acid is precipitated by the addition of a mineral acid or an organic acid and isolated.

Speaking as acids, preferably: sulfuric acid, hydrochloric acid and acetic acid.

Example 1 28.8 g of Ν, Ν-dimethylamino-acrylic acid ethyl ester and 26 g of Ν, Ν-dimethylbenzylamine are heated in 71 ml of toluene to 90 ° C, and at this temperature 40 g of 2,4-dichloro-5-fluorobenzoyl chloride are dropped. within 60 minutes. Next, the mixture is stirred for 15 minutes and the precipitated N, N-dimethylbenzylamine hydrochloride is separated over a suction filter. The filtrate is evaporated in vacuo and 80 ml of butyl glycol are added to the residue. At 70-75 ° C, 13 g of 5 cyclopropylamine are added dropwise over 30 minutes, and upon cessation of the addition, the mixture is kept at 100 ° C for 1 hour until gas evolution ceases. To the reaction mixture is added 27.9 g of potassium carbonate and 100 ml of butyl glycol and heated slowly to 135-145 ° C. Thereby, approx. 40 ml light boiling units. The temperature 10 is kept for 1.5 hours. Next, cool to 100-120 ° C and add 130 ml of water to the reaction mixture. The mixture is stirred at 90 ° C for 15 minutes and at this temperature 27 ml of acetic acid is added dropwise over 15 minutes. The flask contents are cooled and the solid is separated over a suction filter.

The product is washed with 27 ml of water and 50 ml of methanol, dry well and dried for 24 hours at 70 ° C in vacuo.

Yield: 37 g = 74.9% of theory.

EXAMPLE 2 43.2 g of N, N-dimethylamino-acrylic acid ethyl ester are heated in 84 ml of toluene to 100 ° C and 40 ml of triethylamine are added. At reflux temperature, 60 g of 2,4-dichloro-5-fluorobenzoyl chloride is dropped over 30 minutes and then the precipitated triethylamine hydrochloride 25 is separated over a suction filter. Wash with 65 ml of toluene and add to the filtrate dropwise at 70 ° C 16.2 g of cyclopropylamine over 20 minutes. Heat to 100 ° C until gas evolution ceases. Next, 42 g of potassium carbonate and 270 ml of butyl glycol are added and heated slowly to 135-30 145 ° C. Thereby, approx. 180 ml toluene and low boiling

shares. A temperature of 135-145 ° C is maintained for 1.5 hours and after cooling the reaction mixture to 100 ° C 200 ml of water is added. After 15 minutes, drop at 90 ° C

40.5 ml of acetic acid and the precipitated solid are separated by suction over a suction filter. The product is post-washed with 140 ml of water and 75 ml of methanol, dried well and dried for 24 hours in a vacuum at 70 ° C.

Yield·. 58.5 g = 79% of theory.

Example 3 44.7 g of Ν, Ν-dimethylaminoacrylic acid ethyl ester and 17.1 g of N, N'-dimethylpiperazine are heated in 95 ml of refluxing cyclohexane. 62 g of 2,4-dichloro-5-fluoro-benzoyl chloride are added dropwise over 1 hour. The precipitated dimethylbenzylamine hydrochloride is separated over a suction filter and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in 125 ml of butyl glycol and 20.2 g of cyclopropylamine are added dropwise at 90 ° C. After cessation of gas evolution, 43.4 g of potassium carbonate and 165 ml of butyl glycol are added and heated for 1.5 hours to 145 ° C. Thereby, initially 15 small quantities of light boiling proportions are distilled off. After 1.5 hours, cool to 100 ° C, add 205 ml of water and stir for 15 minutes at 95 ° C. Next, 42 g of acetic acid is added dropwise over 15 minutes, cooled to 30 ° C, and the precipitated solid is separated on a 20 suction filter. Wash the cookie cake with 180 ml of water and 80 ml of 80% isopropanol and dry at 70 ° C overnight in vacuum.

Yield: 60.1 g = 78.1% of theory.

Example 4 33.7 g of N, N-dimethylamino-acrylic acid methyl ester are heated with 40.5 g of Ν, Ν-dimethylbenzylamine in 95 ml of toluene to 110 ° C.

At reflux temperature, 62 g of 2,4-dichloro-5-fluorobenzoyl chloride is dropped over 1 hour and then the precipitated dimethylbenzylamine hydrochloride is separated over a suction filter. The solvent is distilled off in vacuo, 130 ml of butyl glycol is added and at 90 ° C 20.2 g of cyclopropylamine are added dropwise over 20 minutes. After the gas evolution ceased, 43.4 g of potassium carbonate and 150 ml of butyl glycol were added to the reaction mixture and slowly heated to 140 ° C.

35 Thus, low quantities of low boiling solvent are obtained. Stir for 1.5 hours at 140 ° C.

11 DK 174855 B1

After cooling to 100 ° C, 205 ml of water is added to the reaction mixture and stirred at 90 ° C for 15 minutes.

Under light cooling, 100 ml of 30% sulfuric acid is added and the solid is separated on a suction filter, washed with 200 ml of water and 200 ml of isopropanol. The solid is dried in vacuo overnight at 70 ° C.

Yield: 59.4 g = 77.2% of theory.

Example 5 To 44.7 g of Ν, Ν-dimethylamino-acrylic acid ethyl ester in 95 ml of cyclohexane is added 55.6 g of tributylamine, and 62 g of 2,4-dichloro-5-fluorobenzoyl chloride are added dropwise over 1 hour. . 250 ml of water are then added to the reaction mixture and the aqueous salt phase is separated. The aqueous phase 15 is stirred once more with 50 ml of cyclohexane and the combined organic phases are evaporated to dryness in water jet vacuum. The residue is taken up with 125 ml of butyl glycol, which is heated to 70 ° C, and in 20 minutes 20.2 g of cyclopropylamine are added dropwise. After cessation of gas evolution, an additional 20 160 ml of butyl glycol and 44 g of potassium carbonate are added and the mixture is slowly heated to 140 ° C. After the mixture has reached a temperature of 140 ° C, stir for 1.5 hours, then cool to 100 ° C and add 205 ml of water to the mixture.

After 15 minutes, 42 g of acetic acid is added dropwise over 10 minutes and cooled to room temperature. The precipitate is isolated over a suction filter and washed with water and isopropanol. After drying at 50 ° C in a vacuum overnight, 54.6 g = 71% of theoretical yield is obtained.

Example 6 In 148 ml of toluene, 105 g of tributylamine and 86 g of Ν, Ν-dimethylamino-acrylic acid methyl ester are heated to 105 ° C, and 124 g of 2,4-dichloro-5-fluoro-benzoyl chloride are added dropwise over 1 hour. After cooling the reaction mixture to 35 ° C, extract with 2 x 250 ml of water. The organic phase is extensively concentrated in water jet vacuum, and to the residue, 37.5 g of cyclopropylamine are added dropwise at an internal temperature of 70-75 ° C. Thereby, gaseous dimethylamine is avoided until the reaction ceases. To the reaction mixture is added 86.8 g of potassium carbonate and 500 ml of 5-butyl glycol and heated slowly to 135-145 ° C. Thereby, low quantities of low boiling solvent are distilled off. The temperature of 135-145 ° C is maintained for 1.5 hours, then cooled to 100 ° C and 535 ml of 10% acetic acid is added dropwise.

The resulting suspension is cooled to room temperature and the solid is separated over a suction filter and washed with 175 ml of water and 200 ml of 80% isopropanol. The product is dried in vacuo overnight at 70 ° C.

Yield: 220 g = 78.1% of theory.

Claims (17)

13 DK 174855 B1 A process for the preparation of quinolone carboxylic acids of the general formula I 5 * 4 s χ, ν ^ - 'Ss ^' '- v'COOH JJTT «» * 2 * 1 * 1 10 wherein R 1 is propyl, cyclopropyl, isopropyl or vinyl, X1 means fluorine, chlorine, Br, CN, NO2 or hydrogen, and X2, X3 and X4 mean fluorine, chlorine, NO2 or hydrogen, characterized in that a compound is reacted with a so-called batch reaction without isolation of 15 intermediate steps. the formula II Jt X3N ^^ y ^ C ° Cl2O AA <n) X2 T X5 * 1 wherein X1 to X4 have the above meaning and means halogen, especially chlorine or fluorine, with a compound of formula III CH-COOR2 II ,. (H1) ch-nr3r3 wherein R2 and R3 are the same or different and mean alkyl, in the presence of a solvent and a base, optionally under heating to 50-150 ° C, to form a compound of formula IV B1 x4 oo JL * il, X3YVc'S'c'or2 _i · AI ·, (iv) 5 chnr3r3 χ2 In x5 * 1, this compound of formula IV undergoes an amine exchange 10 at temperatures of 50-120 ° C in the presence of the above solvents and in the presence of an amine of formula R 1 NH 2 wherein R 1 has the above meaning to give a compound of formula V 15 MI, x0Orr xfrNrNH'Ri X1 20 having the above symbolic meanings, and then the compound of formula V at temperatures between 80 and 180 ° C in the presence of a base, saponifies and precipitates the compound of formula I by the addition of acid. 2. Process for Preparation of Quinolone Carboxylic Acids of General Formula I X4 o ΙχΧΤ (i) 30. X1 wherein ίΟ- means cyclopropyl, X1 means fluorine, chlorine, Br, CN, NO2 or hydrogen, and X2, X3 and X4 means fluorine, chlorine, NO2 or hydrogen, characterized by. that, without isolating intermediate steps in a so-called batch reaction, a compound of formula II is reacted with the formula II: X 1 wherein X 1 to X 4 has the above meaning and X 5 means halogen, especially chlorine or fluorine, with a compound of formula III CH-COOR2 II. , wherein your R-and Rr are the same or different and means C ^-C4 alkyl, in the presence of a solvent and a base, optionally under heating to 50-150 ° C, to form a compound of formula IV X4 0 0 20 S * II I. xaVVC'c-C'0R2 xjXjXjKMR3R3 2 * 1 This compound of formula IV undergoes an amine exchange at temperatures of 50-120 ° C in the presence of the above solvents and in the presence of cyclopropylamine to form a compound of formula V Xa o 30 JL u ii, x3Nrvr'S * c "° R Jl JL Η (V) / V \ CH-NH-R, χ2 I x5 xi 35 having the above symbolic meanings, and then the compound of formula V terminates at temperatures between 80 and In the presence of a base, the compound of formula I saponifies and precipitates by the addition of acid. A process for preparing quinolone carboxylic acids of the general formula (I) X1 R1 wherein R1 represents cyclopropyl, X1, X2 and X3 are the same or different and represent fluorine or chlorine, and X4 means hydrogen, characterized in that, without isolation of intermediate steps in a so-called batch reaction, a compound of formula II f * (11> xi 25) wherein X1 to X4 is as defined above and X4 is halogen, especially chlorine or fluorine , with a compound of formula III CH-COOR 2 in. * o (Π1) CH-NR 3 R 3 wherein R 2 and R 3 are the same or different and represent C 1 -C 4 alkyl, in the presence of a solvent and a base, optionally under heating to 50-150 ° C, to form a compound of formula IV 17 DK 174855 B1 Μ Ϊ a ^ YYtc 0R nv> gHNR3R3 This compound of formula IV undergoes an amine exchange at temperatures of 50-120 ° C in the presence of the aforementioned solvents and in the presence of cyclopropylamine, whereby a compound of formula V is formed. > IY "C" S "C" R 15 Λ2 IX X1 having the above symbolic meanings, and then the compound of formula V, at temperatures between 80 and 180 ° C, in the presence of a base, saponifies and precipitates the compound ice of formula I by the addition of acid. A process for the preparation of quinolone carboxylic acids of the general formula I X4 0 25 ^ vVr00 ”l (Jt Π (i) * 2 * in Ri wherein R 1 is cyclopropyl, X 1 and X 4 are hydrogen, X 3 is fluorine, and X 2 is chlorine, characterized in that a compound of formula II is reacted without an isolation of 35 intermediate steps in a so-called batch reaction XgvXV'COCl 3 Wherein X1 to X4 have the above meaning, X5 means halogen, especially chlorine or fluorine, with a compound of formula III f'coa * z <m> ch-nr3r3 wherein r2 and R3 are the same or different and means C ^-C ^ j alkyl, in the presence of a solvent and a base, optionally under heating to 50-150 ° C, to form a compound of formula IV x4 p x3'Y''V'C'S'C'0R JL JL "* * <iv> gHNR3R3 undergoes this compound of formula IV undergoes an amine exchange at temperatures of 50-120 ° C in the presence of the above solvents and in the presence of cyclopropylamine to give a compound of formula V X 30 J #, Χ3Υί Tc'or2 JJ i · on / γ \ CH-NH-Rj χ2 TX * 1 * 1 35 having the above symbolic meanings, and then the compound of formula V at temperatures between 80 and 19 DK-180 ° C C in the presence of a base, the compound of formula I saponifies and precipitates by the addition of acid. A process for the preparation of quinolone carboxylic acids of the general formula I 5 * 4 0 τςτ ”ίο 2 Riι Ri wherein R 1 is cyclopropyl, X 1 and X 2 are chlorine, X 3 is fluorine, and 15 X 4 is hydrogen, characterized in that without isolation of intermediate steps in a so-called batch reaction, a compound of formula II X4 converts 20 p wV- (II) * 2 * 1 X 25 wherein X compound of formula III CH-COOR2 II (III) 30 CH-NR 3 R 3% wherein R 2 and R 3 are the same or different and mean ^ C This compound of formula IV undergoes an amine exchange at temperatures of 50-120 ° C in the presence of the above-mentioned solvents and in the presence of cyclopropylamine to form a compound of formula Vjb «8 2 ^ YV-r0R tv) 15 gH-NH-Rj X9 IX ° having the above symbolic meanings, and then the compound of formula V terminates at temperatures between 80 and 20 180 ° C in the presence of a base, saponifies and precipitates the compound of formula I by the addition of acid.