KR20010018722A - Ethyl 2,3,5-trifluoro-4-(4-methyl-1-piperazinyl)benzoylacetate and a process for preparing thereof - Google Patents

Abstract

PURPOSE: Provided is a method for manufacturing ethyl 2-£2,3,5-trifluoro-4-(4-methyl-1-piperazinyl)|benzoyl-3(S)-(1-hydroxyprophy-2-nilamino) acrylate more easily in a high yield. The compound is used in manufacturing an antibacterial agent, Levofloxacin, as an intermediate. CONSTITUTION: Ethyl 2-£2,3,5-trifluoro-4-(4-methyl-1-piperazinyl)|benzoyl-3(S)-(1-hydroxyprophy-2-nilamino) acrylate represented by the formula (1) is manufactured by the following steps of: i) reacting ethyl 2,3,5-trifluoro-4-(4-methyl-1-piperazinyl)benzoyl acetate of the formula (2) with triethyl orthoformate of the formula (3) under a nonpolar solvent at 20-200 deg.C, preferably 100-120 deg.C, for 2-50 hours, preferably 22-28 hours, to obtain an intermediate of the formula (4); and ii) reacting the intermediate of the formula (4) with (S)-(+)-2-amino-1-propanol having optical activity under a polar solvent at 0-100 deg.C, preferably 10-30 deg.C, for1-10 hours, preferably 2-3 hours, to obtain ethyl 2-£2,3,5-trifluoro-4-(4-methyl-1-piperazinyl)|benzoyl-3(S)-(1-hydroxyprophy-2-nilamino) acrylate.

Description

Ethyl 2- [2,3,5-trifluoro-4- (4-methyl-1-piperazinyl)] benzoyl-3 (S)-(1-hydroxypropy-2-ylamino) acrylate and Method for preparing the same {Ethyl 2,3,5-trifluoro-4- (4-methyl-1-piperazinyl) benzoylacetate and a process for preparing persons}

The present invention is ethyl 2- [2,3,5-trifluoro-4- (4-methyl-1-piperazinyl)] benzoyl of the formula (1) which can be used as an intermediate in the preparation of a medicament useful as an active antimicrobial agent. -3 (S)-(1-hydroxypropy-2-ylamino) acrylate and a method for producing the same.

The compound of Formula 1 is a compound having optical activity, and a method for preparing a racemate of the compound is disclosed in Korean Patent Publication No. 92-12087.

According to the above technique, the ethyl 2,3,5-trifluoro-4- (4-methyl-1-piperazinyl) benzoyl acetate of formula (2) is a dimethylformamide dimethylacetal and racemate of formula (12) Is reacted with 2-amino-1-propanol of ethyl 2- [2,3,5-trifluoro-4- (4-methyl-1-piperazinyl)] benzoyl-3- (1-hydride) Roxypropy-2-ylamino) acrylate can be obtained.

However, the preparation method of Scheme 1 has a problem that the compound of Formula 12, which is a starting material, is expensive and very sensitive to moisture, and reacts with a highly flammable solvent such as toluene, which is inappropriate for industrial application.

The present inventors have made a lot of research and efforts to solve the above problems, and as a result, have found a new material and a method for preparing the same, which is simpler and higher in yield.

An object of the present invention is ethyl 2- [2,3,5-trifluoro-4- (4-methyl-1-piperazinyl)] benzoyl-3 (S)-(1-hydroxypropyn-2-yl Amino) acrylate and its manufacturing method are provided.

The present invention provides ethyl 2- [2,3,5-trifluoro-4- (4-methyl-1-piperazinyl)] benzoyl-3 (S)-(1-hydroxypropy-2) -Nylamino) acrylate and a method for preparing the same.

The preparation method of the compound of Formula 1 will be described with reference to Scheme 2 below.

In Scheme 2, a non-polar solvent is substituted with ethyl 2,3,5-trifluoro-4- (4-methyl-1-piperazinyl) benzoyl acetate of Formula 2 and commercially available triethyl olsoformate of Formula 3 Under the reaction temperature of 20 ~ 200 ℃, preferably 100 ~ 120 ℃ 2 to 50 hours, preferably 22 to 28 hours to prepare a compound of formula (4) as an intermediate, the formula 5 having an optical activity Under reaction of (S)-(+)-2-amino-1-propanol with polar solvent at a reaction temperature of 0 to 100 캜, preferably 10 to 30 캜 for 1 to 10 hours, preferably 2 to 3 hours. Compounds can be prepared simply in quantitative high yields.

Meanwhile, the compound of Formula 2 is reacted with triethyl olsopromate under a non-polar solvent to obtain the compound of Formula 4, and then only the non-polar solvent is removed under reduced pressure without separation, followed by reaction with the compound of Formula 5 under a polar solvent. It is also possible to obtain.

Examples of the nonpolar solvent used in the above method include a solvent selected from the group consisting of toluene, benzene and hexane, or a mixed solvent obtained by mixing two or more thereof.

Examples of the polar solvent used in the above method include a solvent selected from the group consisting of dimethyl sulfoxide, dimethylformamide, dimethylacetamide, acetonitrile, water and ethanol solvent, or a mixed solvent obtained by mixing two or more thereof. have.

In Scheme 2, the compound of Formula 2 used as a starting material is a known compound [see Chem. Pharm. Bull., Vol. 34, 4098-4102 (1986)] can be prepared simply from tetrafluorobenzoyl chloride represented by the following formula (6).

In addition, in Scheme 2, the compound of Formula 5 having optical activity can be easily obtained from nature by reducing L-Alanine of Formula 10, which is inexpensive as in Scheme 4, using a reducing agent.

Reducing agents used in the above method may include lithium aluminum hydride, boron trifluoro, ranickel or sodium borohydride.

As described above, ethyl 2- [2,3,5-trifluoro-4- (4-methyl-1-piperazinyl)] benzoyl-3 (S)-( 1-hydroxypropy-2-ylamino) acrylate is a (-)-9-fluoro-2,3-dihydro-3 (S) -methyl-10- (4) -Methyl-1-piperazinyl) -7-oxo-7H-pyrido [1,2,3-de] -1,4-benzoxazine-6-carboxylic acid (levofloxacin; Levofloxacin) Can be used as

The present invention is explained in more detail with reference to the following examples, but these are not limitative of the present invention.

Example 1: Preparation of (S)-(+)-2-amino-1-propanol

A solution of 75.9 g (2 mole) of lithium aluminum hydride suspended in 100 ml of tetrahydrofuran was cooled to 0 ° C., 89.1 g (1 mole) of L-alanine was slowly added dropwise, and then heated to 60 ° C. and vigorously stirred for 24 hours. I was. After the reaction was completed, the mixture was cooled to 0 ° C., and 360 ml of water and 90 ml of 15% sodium hydroxide solution were sequentially added thereto, followed by vigorous stirring to remove the precipitate by filtration. The reaction mixture was dried over magnesium sulfate and distilled under reduced pressure to remove tetrahydrofuran to give 61.6 g (82%) of (S)-(+)-2-amino-1-propanol.

IR: υ _max (cm ^-1 ): 3,345, 3,307, 3,160, 1,621, 1,593

H ¹ NMR (CDCl ₃ , 300 MHz) (ppm):

1.03 (3H, d, = CHCH ₃ ), 2.79 (1H, m, -OH),

2.98 (1H, m, = CHCH ₃ ), 3.23 (2H, t, -NH ₂ ),

3.51 (2H, d, -CH ₂ OH)

[α] _D = + 18 ° (c = 1.8, H ₂ O)

Example 2: Preparation of ethyl 2,3,4,5-tetrafluorobenzoyl acetate

357.4 g (2.1 mole) diethylmalonate potassium salt, 238.1 g (2.5 mole) magnesium chloride and 222.6 g (2.2 mole) triethylamine were suspended in 5,000 ml of acetonitrile. After stirring for 2 hours, 212.6 g (1 mole) of tetrafluorobenzoyl chloride was slowly added dropwise thereto, followed by vigorous stirring at room temperature for 24 hours. After the reaction was completed, the mixture was distilled under reduced pressure to remove acetonitrile, 1,500 ml of toluene and 1,500 ml of 2N hydrochloric acid solution were injected, stirred vigorously, neutralized with 2N-sodium hydroxide aqueous solution, and the organic layer was separated. The reaction mixture was dried over magnesium sulfate, distilled under reduced pressure to remove the solvent, and the residue was crystallized with heptane to give 256.3 g (94%) of pale yellow ethyl 2,3,4,5-tetrafluorobenzoyl acetate.

Melting Point: 63 ~ 64 ℃ (dec.)

IR: υ _max (cm ^-1 ): 1,735, 1,644, 1,615

H ¹ NMR (CDCl ₃ , 300 MHz) (ppm):

1.31 (3H, m, -OCH ₂ CH ₃ ), [3.96 (d), 5.84 (s), 12.71 (s)] (2H, -CH _2- ),

4.26 (2H, m, -OCH ₂ CH ₃ ), 7.56 (1H, aromatic H)

Example 3: Preparation of ethyl 2,3,5-trifluoro-4- (4-methyl-1-piperazinyl) benzoyl acetate

2,000 ml of acetonitrile in 264.2 g (1 mole) ethyl 2,3,4,5-tetrafluorobenzoyl acetate, 150.3 g (1.5 mole) 4-methyl-piperazine and 84.01 g (1.5 mole) sodium bicarbonate The solution that was clouded on was heated to 90 ° C. and vigorously stirred for 3 hours. After completion of the reaction, distillation under reduced pressure was carried out to remove acetonitrile, 1,000 ml of water and 1,000 ml of chloroform were injected thereto, followed by vigorous stirring to separate the chloroform layer, followed by washing with the same amount of water. The reaction mixture was dried over magnesium sulfate, distilled under reduced pressure to remove the solvent, and the residue was crystallized from hexane to give a slightly yellow ethyl 2,3,5-trifluoro-4- (4-methyl-1-piperazinyl) benzoyl acetate. 316.8 g (92%) were obtained.

Melting Point: 60 ~ 61 ℃ (dec.)

IR: υ _max (cm ^-1 ): 1,746, 1,673, 1,620

H ¹ NMR (CDCl ₃ , 300 MHz) (ppm):

1.27 and 1.33 (3H, m, -OCH ₂ CH ₃ ), 2.34 (3H, s, = NCH ₃ ),

2.49 to 2.57 (4H, m, piperazine H), 3.32 to 3.44 (4H, m, piperazine H),

[3.91 (d), 5.78 (s), 12.64 (s)] (2H, -CH _2- ),

4.22 and 4.26 (2H, each q, -OCH ₂ CH ₃ ), 7.29-7.36 (1H, aromatic H)

Example 4: Preparation of ethyl 2- [2,3,5-trifluoro-4- (4-methyl-1-piperazinyl)] benzoylacrylate

2,000 ml of toluene in 344.3 g (1 mole) of ethyl 2,3,5-trifluoro-4- (4-methyl-1-piperazinyl) benzoyl acetate and 296.4 g (2 mole) of triethylolsoformate The solution dissolved in was heated to 110 ° C. and stirred for 24 hours. After the reaction was completed, 1,000 ml of water was added thereto, and vigorously stirred, the toluene layer was separated, and washed with the same amount of water again. The reaction mixture was dried over magnesium sulfate, distilled under reduced pressure to remove the solvent, and 323.5 g (99%) of ethyl 2- [2,3,5-trifluoro-4- (4-methyl-1-piperazinyl) ] Benzoyl acrylate was obtained.

IR: υ _max (cm ^-1 ): 1692, 1666, 1624, 1593

H ¹ NMR (CDCl ₃ , 300 MHz) (ppm):

0.92 and 1.26 (6H, t, —CO ₂ CH ₂ CH ₃ , and CHOCH ₂ CH _{3, respectively} ),

2.41 (3H, s, -NCH ₃ ), 2.28-2.43 (4H, m, piperazine H),

3.52-3.70 (4H, m, piperazine H),

4.15 and 4.49 (4H, q, -CO ₂ CH ₂ CH ₃ , and = CHOCH ₂ CH _{3, respectively} ),

6.74-6.85 (1H, m, Directional H),

8.21 and 8.32 (1H, d, = CHO- respectively)

Example 5: Ethyl 2- [2,3,5-trifluoro-4- (4-methyl-1-piperazinyl)] benzoyl-3 (S)-(1-hydroxypropy-2-ylamino Production of acrylate

344.3 g (1 mole) of ethyl 2,3,5-trifluoro-4- (4-methyl-1-piperazinyl) benzoyl acetate and 296.4 g (2 mole) of triethylolsoformate in 2,000 ml of toluene The dissolved solution was heated to 110 ° C., stirred for 24 hours, toluene was distilled off under reduced pressure, and then dissolved in 2,000 ml of ethanol. 112.7 g (1.5 mole) of (S)-(+)-2-amino-1-propanol was slowly added dropwise thereto, followed by vigorous stirring at room temperature for 3 hours. After completion of the reaction, the reaction mixture was distilled under reduced pressure to remove ethanol, and 420.8 g (98%) of ethyl 2- [2,3,5-trifluoro-4- (4-methyl-1-piperazinyl)] benzoyl-3 ( S)-(1-hydroxypropy-2-ylamino) acrylate was obtained.

IR: υ _max (cm ^-1 ): 1,681, 1,668, 1,625

H ¹ NMR (CDCl ₃ , 300 MHz) (ppm):

0.98 and 1.09 (3H, t, -OCH ₂ CH ₃ ), 1.35 (3H, d, -NHCHCH ₃ ),

1.80-2.20 (1H, br, -OH), 2.35 (3H, s, = NCH ₃ ),

2.30 to 2.65 (4H, m, piperazine H), 3.20 to 3.50 (4H, m, piperazine H),

3.40 to 3.60 (3H, m, = NCHCH ₂ O-), 4.03 and 4.07 (2H, q and -OCH ₂ CH ₃ ),

6.80 to 6.70 (1H, m, aromatic H), 8.15 and 8.20 (1H, d, = CHN =),

9.20-9.70 and 10.50-11.00 (1H, respectively br, = NH)

[α] _D = -68.3 ° (c = 0.12, CHCl ₃ )

Ethyl 2- [2,3,5-trifluoro-4- (4-methyl-1-piperazinyl)] benzoyl-3 (S)-(1-hydroxypropy) prepared by the preparation method of the present invention. 2-Nylamino) acrylate can be usefully used as an intermediate in the preparation of levofloxacin, a drug useful as an antibacterial agent.

Claims (9)

A method of preparing a compound of formula 1 by reacting a compound of formula 4 with a compound of formula 5 The method of claim 1, wherein the polar solvent is a solvent selected from the group consisting of dimethyl sulfoxide, dimethylformamide, dimethylacetamide, acetonitrile, water and ethanol solvent, or a mixed solvent of two or more thereof. How to The method according to claim 1, wherein the reaction temperature is 0 to 100 ° C. The method of claim 1, wherein the compound of formula 4 is obtained by reacting a compound of formula 2 with a compound of formula 3 in a nonpolar solvent. The method according to claim 4, wherein the nonpolar solvent is a solvent selected from the group consisting of toluene, benzene and hexane, or a mixed solvent in which two or more thereof are mixed. The production method according to claim 4, wherein the reaction temperature is 20 to 200 ° C. The method of claim 1, wherein the compound of formula 5 is obtained by reacting the compound of formula 10 with a reducing agent. 8. The method of claim 7, wherein the reducing agent is lithium aluminum hydride, boron trifluoride, Raney nickel or sodium borohydride. A compound of formula 1