SU1395139A3 - Method of producing derivatives of acrylic acid - Google Patents

Abstract

This invention relates to a process for the preparation of acrylic acid (AA) derivatives of the formula

Description

where R, - QN, -COOR, where R is methyl or ethyl; Rj and R are the same methyl or ethyl; X and X - F, C1; X - H, F, which is the product for the synthesis of ciprofloxacin. The preparation of the target compounds is carried out from the acid halide and amine derivative at a temperature from cognate to the boiling point of the reaction mixture in an anhydrous organic solvent in the presence of an acid acceptor - tertiary amine. The method provides an increase in yield up to 70-79% (against 62%).

(I

The invention relates to a method for producing new acrylic acid derivatives of the general formula O

C-C,

 l

Rj 2

where R is SI, COOH, where R4 is methyl or ethyl;

K and B are the same and mean methyl or ethyl;

X and X - fluorine, chlorine;

X is hydrogen, fluorine, which can be used as intermediates for the synthesis of ciprofloxacin ..

The purpose of the invention is to develop a method for producing new acrylic acid derivatives - intermediates for obtaining ciprofloxacin, which allow to simplify the method of its preparation.

An example. Methyl 3 dimethylamino-2-C2,4-dichloro-5-fluorobenzoyl) acrylic acid

COOCHj

Sc,

To a solution of 22.75 g of 2,4-dichloro-5-β-fluorobenzoyl chloride in 80 ml of anhydrous dioxane, cooling with ice and stirring, add a solution of 12.9 g of methyl 3-dimethylaminoacrylic acid ester in 25 ml of dioxane and then 10.5 g of triethylamine. The mixture is stirred at room temperature for 3 hours, heated to 50 ° C for one hour, the solvent is distilled off in vacuo, and the residue is extracted with methylene chloride - water.

The phases are separated, and the aqueous phase is further extracted with methylene chloride. The combined organic phases are washed with water, dried over sodium sulfate and the methylene chloride removed in vacuo. The crystalline residue is recrystallized from methanol — water. Obtain 28.5 g (89% of theory) of methyl 3-dimersamino-2

- (2,4-dichloro-5-fluorobenzoyl) acrylic acid with m. Pl. 107 - 109 S. Mol. 320.2.

Calculated,%: C, 48.76; H 3.77; C1 22.14; N 4j37.

C ,, H ,,

Found,%: C 48.6; H 3.8; C1 22.1; N 4.2.

Example 2. 3-dimethylamino-2- (2,4-dichloro-5-fluorobenzoyl) acrylic acid ethyl ester

To a solution of 22.75 g of 2,4-dichloro-5- -fluorobenzoyl chloride in 100 ml of anhydrous dioxane at 10-20 ° C, 14.3 g of ethyl 3-dimethylaminoacryloic acid and 10.5 g are added dropwise with stirring. triethylamine. Stir for 3 hours at room temperature, heat for 2 hours at 40-50 ° C, distill off the solvent in vacuo and absorb the residue with a mixture of methylene chloride, orid-water. The phases are separated and the aqueous phase is further extracted with methylene chloride. The methylene chloride solution is washed with water, dried over sodium sulfate, and the solvent is removed in vacuo.

The crystalline residue is recrystallized from cyclohexane - light gasoline. 30.8 g (92.3% of theory) of ethyl 3-dimethylamino-2- (2,4-dichloro-5-fluorobenzoyl) acrylic acid ethyl ester are obtained with a melting point of 200 mg. 94 - 95 S. Mol. 334.2.

Calculated,%: C 50.31; n 4.22; F 5.68; N 4.19.

C, 4H, 4Cl5, FN05

Found,%: C 50.4; H 4.2; F 5.5; N 4, K

Example 3. Nitrile of 3-dimethyl-amino-2- (2,4-dichloro-5-fluorobenz oyl) acrylic acid

To a solution of 22.75 g of 2,4-dichloro-5-β-fluorobenzoyl chloride in 100 ml of toluene, cooled with ice and stirring, 9.6 g of 3-dimethylaminoacrylonitrile and 10.5 g of triethylamine are added dropwise. Stir for one hour at room temperature and then boil for a while under reflux. The solvent is then distilled off in vacuo and the residue is extracted with methylene chloride-water, the methylene chloride phase is washed with water, dried with sodium sulfate and concentrated is evaporated in vacuo. The crystalline residue is recrystallized from ethanol. This gives 26.4 g (92% of theory) of 3-dimethylamino-2- (2,4-dichloro-5-fluorobenzoyl) acrylic acid nitrile with t, Br1, 138-139 Cc Mol, m, 287.1,

Calculated,%; C 50.19; H 3.15; C1 24.70; N 9.75,

С, 1Н, С1гГК О-. -.

Found,%: C 50.3; H 3.1; C1 24.6s N 9.8,

Example 4, 3-diethylamino-2- (2,4-dichloro-5-fluorobenzoyl) acrylic acid ethyl ester

ABOUT

c-o-cooCaHs ", SI

C1 I

N

To a solution of 22.75 g of 2,4-dichloro-5- -fluorobenzoyl chloride in 80 mp of anhydrous dioxane, cooling with ice and stirring, add 17.1 g of ethyl 3-diethylaminoacrylic ester and then 10.5 g of triethyl - amine. Stir for one hour at room temperature, boil for 45 minutes under reflux, distill off the solvent in vacuo and then extract the oily residue with methylene chloride-water, separate the phases and separate the aqueous solution with additional methylene chloride. The combined organic phases were washed with water, dried with sodium sulfate and the methylene chloride removed in mind. This gives 29 g (80.1% of theory) of 3-diethypamino-2-t 2,4-dichloro-5-fluorobenzonyl) acrylic acid ethyl ester as a brown oil, Mol, m, 362.2,

39

Calculated,%: C 53.05; H 5.00; C1 19.57; N 3.86,

C ,, H ,,

Found,%: C 52.9; H 4.9; C1 19.6; N 3,8,

Example 5, Nitrile-3-dimethyl-amino-2- (2,3,4,5-tetrafluorobenzoyl) acrylic acid

To a solution of 21.25 g of 2,3,4,5-tetrafluorobenzoylsloride a in 75 ml of anhydrous dioxane, cooled with ice, after stirring at approximately 10 -15 Ci, 9.7 g of 3-dimethylaminoacrylonitrile are added dropwise and then 10 , 5 g of triethylamine. The mixture is boiled under reflux for 4 hours and then the solvent is distilled off in vacuo and the residue is extracted with methylene chloride - water. The phases are separated and the aqueous is further extracted with methylene chloride. The combined organic phases are washed with water, dried over sodium sulfate and the methylene chloride is removed in vacuo. After recrystallization of the crystalline residue from ethanol, 23.5 g (86.4% of theory) of 3-dimethylamino-2- (2,3,4,5-tetrafluorobenzoyl) acrylic acid nitrile are obtained with m, mp, 149-15 G, Mol , m, 258.2, Calculated,%: C 55.81; H 3.12; F 29.43; H 5.42,

Found, L: C 55.9; H 3.1; F 29.2; N 5.3

Example 6 The process is carried out as in Example 1, but in anhydrous toluene in the presence of pyridine. You get 29 g (90.6% of theory) of methyl 3-dimethylamino-2- (2,4-dichloro-5-fluorobenzoyl) acrylic acid with t, mp, 107 - 109 ° C,

Example 7 The process is carried out analogously to example 2, but in anhydrous toluene in the presence of pyridine or in anhydrous ansTOisa in the presence of pyridine, or in anhydrous toluene in the presence of 4K solution of 30 g of the target product

Stage I, 100 MP of anhydrous dioxane, was added in portions of 3.25 g of 80% sodium nitride, while cooling with ice and stirring. Then, stir at room temperature for 30 minutes and at the boiling point of the mixture for 2 hours. After distillation of dioxane in vacuum, the residue is suspended in 150 ml of water, mixed with 6.25 g

A mixture of 26.4 g of 3-dimethylamino-2- (2,4-dicloro-5-fluorobenzyl) acrylic acid nitrile and 5.9 g of cyclopropylamine in 80 ml of toluene is heated under reflux for 30 minutes.

after which the gas is completed. The toluene is distilled off in vacuo and the residue is recrystallized from a mixture of ethanol and light gasoline. 25.4 g of 3-cyclopropylamino-2- (2,4-dichloro-5-fluorobenososh) acrylic acid nitrile are obtained, with an mp. 94 -.

Stage II. 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid nitrile O

BUT

to a solution of 25.4 g of the desired product of stage I in 70 ml of dimethylformamide

13.4 g of potassium carbonate is added and the mixture is heated at 3 hours. The reaction mixture is poured onto ice, the precipitate is filtered off with suction and washed with water. After drying in vacuum at 100 ° C., 24.3 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid nitrile are obtained. square 239 - 241 ° С.

Stage III. 7-Chlr-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid

soon

A mixture of 24.3 g of the desired product of stage II, 90 ml of concentrated sulfuric acid and 110 ml of water is heated at 130-135 ° C for 3 hours. The hot solution is poured onto ice, the precipitate is filtered off with water, washed with water and dissolved in 250 ml of 10% sodium hydroxide solution and 250 ml of water when heated. The hot solution is filtered, washed with hot water and adjusted to pH 1 with hydrochloric acid (1: 1). The precipitate is filtered off with suction, washed with water and dried at 100 ° C in vacuo. After recrystallization from a mixture of monomethyl ether, glycol and ethanol, 23.2 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-DIHYDRO-4-OXO-3-CHINOLIN-carboxylic acid, Art. square 240 - 24G.

Stage IV. 1-Cyclopropyl-6-fluoro -1, 4-di idpo-4-oco-7- (1 piperazi

Nile) -3-quinolinecarboxylic acid-i a (ciprofloxacin)

Cun

YU

five

20

25

zo

five

Q.

0

five

A mixture of 23.2 g of the desired product of stage III, 35.5 g of anhydrous piperazine and 100 ml of dimethyl sulfoxide is heated at 135-140 ° C for 2 hours. The solvent is distilled off on average, the residue is suspended in water and washed with water. To the wet product, 100 ml of water are added, boiled, sucked off at room temperature, washed with water and dried over calcium chloride at 1.00 ° C until the weight is constant in a vacuum dryer. 23.1 g are obtained (70.1% of theory, in terms of rta 2,4-dichloro-5-fluorobenzosch-chloride, used to synthesize the starting nitrile of stage I 1-cyclopropyl-6-fluoro-1,4-dihydro- 4-oxo-7- (1- -piperazinyl) -3-quinolinecarboxylic acid with mp 255-257 ° C (decomposed).

Example 10 (comparative). Synthesis of ciprofloxacin zo by a known method.

A. Preparation of the starting 2,4-dichloro-5-fluorobenzoylmalonic acid diethyl ester

WITH SOOSgNe V-C- CH

COOCsTls

23.3 g of magnesium shavings are suspended in 50 ml of anhydrous ethanol. 5 ml of carbon tetrachloride are added and after the start of the reaction 160 g of malonic acid diethyl ester, 100 ml of absolute ethanol and 400 ml of anhydrous ether are added dropwise. At the same time, intense reflux is observed. After the end of the reaction, the mixture is heated under reflux for another 2 hours, cooled to (-5) - (-10) C with dry ice and acetone, and at this temperature a solution of 227.5 g is slowly added dropwise. , 4-dichloro-5-fluoro-benzoyl chloride in 100 ml of absolute

simple ether. Stir at O-C-5) C for 1 hour, allow the mixture to warm to room temperature overnight, and then, while cooling with ice, add a mixture of 400 ml of ice water and 25 ml of concentrated sulfuric acid. The phases are separated and extracted twice with ether. The combined ethereal njjo extracts are washed with a saturated solution of sodium chloride, dried over sodium sulfate and the solvent is distilled off in vacuo. 349.5 g of crude 2,4-dichloro-5-fluorobenzoylmalonic acid are obtained.

Bi. Synthesis of ciprofloxacin.

Stage I. 2,4-Dichloro-5-fluorobenzoyl-acetic acid diethyl ester

С-СН2СООС2Н5

An emulsion of 349.5 g of the crude ester according to A in 500 ml of water is mixed with 1.5 g of p-toluenesulfonic acid. With vigorous stirring, the mixture is heated under reflux for 3 hours, the cooled emulsion is extracted five times with methylene chloride, the combined methylene chloride phases are washed with a saturated sodium chloride solution, dried over sodium sulfate and the solvent is distilled off in a vacuum. After fractionation of the residue in an average vacuum, 218 g are obtained with / 1 sin

2,4-dichloro-5- -fluorobenzoyl-acetic acid ethyl ester with m.p. at 0.09 mbar 127 - 142 ° C.

Stage II. 2- (2,4-Dichloro-5-fluoro-benzoyl) -3--ethoxyacrylic acid diethyl ester

C-COOCgHs

sn

OS2N5

A mixture of 218 g of the desired product of stage I, 172 g of ethyl ester of formic acid and 192 g of acetic anhydride is heated at 150 ° C for 2 hours. The volatile components are successively distilled off in a vacuum created by a water-jet pump and in an average vacuum at a temperature of -baths

120 C.

260.4 g of crude 2- - (2,4-dichloro-5-fluorobenzoyl-3-ethoxyacrylic) acid ethyl ester is obtained as a residue.

Stage III. 2- (2,4-dichloro-5-fluorobenzoyl) -3 cyclopropylaminoacrylic acid ethyl ester

About II

C-C-COOC HS F

C1

HN

To a solution of 260.4 g of the desired product of stage II in 750 ml of ethanol, 45 g of cyclopropyl-amine are added dropwise with ice-cooling and stirring. After completion of the exothermic reaction, the mixture is stirred at room temperature for another 1 h, the solvent is distilled off in vacuo and the residue is recrystallized from a mixture of cyclohexane and petroleum ether. Obtain 239.5 g of ethyl 2- (2,4-dichlor-5-fluorobenzoyl) -3-cyclopropylaminoaccharcic acid ethyl ester. square 89 - 90 ° C.

Stage IV. 7-Chloro-1-cycloprop-1-6-fluoro-1,4-DIHIDRO-4-OXO-3-CHINOLIN-carboxylic acid

soon

To a solution of 239.5 g of the desired product of stage III in 700 ml of anhydrous dioxane, 25.8 g of 80% sodium hydride are added in portions while cooling with ice and stirring. Then stir at room temperature for 30 minutes and at the boiling point of the mixture for 2 hours. Dioxane is distilled off in vacuo, the residue is suspended in 1000 ml of water, 50 g of sodium hydroxide is added and the mixture is heated under reflux for 90 minutes. The warm solution is filtered and washed with water. Then, while cooling with ice, the pH of the medium is adjusted to 1-2 by adding semi-concentrated hydrochloric acid, the precipitate is sucked off, washed with water and dried in vacuum at 100 C. Obtain 208 g of 7-chloro-1-cycloprop150

55

 . 1395139

-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid Art. square 234,237 c.

Step V. 1-Cyclopropyl-6-fluoro--1,4-dihydro-4-oxo-7- (1-piperazinyl-3-quinolinecarboxylic acid

soon

A mixture of 208 g of the desired product of stage IV, 318 g of anhydrous piperazine and 800 MP of dimethyl sulfoxide is heated at 135-140 ° B for 2 hours. The solvent is distilled off under medium vacuum, the residue is suspended in water, sucked off and washed with water. 800 ml of water are added to the wet raw product, boiled, sucked off at room temperature, washed with water and dried over calcium chloride until constant mass at 100 ° C in a vacuum dryer. 206 g (62.2% of theory, in terms of 2,4-dichloro-5-fluorobenzoyl chloride, used to synthesize the starting malonic acid diethyl ester) are obtained. 1-cyclopropyl-6-fluoro-1,4-DIHYDRO-4 - -oxo-7- (1-piperazinyl) -3-quinoline-carboxylic acid with so pl. 255 - 257 C (decomposed).

A comparison of the data of examples 1-10 shows that the method using new derivatives of acrylic acid allows us to simplify the method of obtaining ciprofloxacin and to obtain it with a higher yield of 70-79% versus 62% in the known method.

20

thirty

15

X and X - fluorine, chlorine;

X is hydrogen, fluorine, characterized in that the compound of the general formula

25

35

40

gr, e Hal - halogen;

X, X and X are indicated above, are reacted with a compound of the general formula

HC-R, (I

CH I

: N

Rg {5

Claims (1)

Formula inventions The method of obtaining derivatives of acrylic acid of the General formula where .RJ, R and Rj - are indicated above; at temperatures from room to dark and boiling point of the reaction mixture in an anhydrous organic solvent in the presence of an acid acceptor - a tertiary amine. 12 where R, - CN, -COOR4, where R is methyl or ethyl;   3 are the same, methyl or ethyl; X and X - fluorine, chlorine; X is hydrogen, fluorine, characterized in that the compound of the general formula gr, e Hal - halogen; X, X and X are indicated above, are reacted with a compound of the general formula HC-R, (I CH I : N Rg {5