KR20010078569A - A process for producing ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-3(S)-(1-hydroxyprop-2-ylamino)acrylate and intermediate compound thereof - Google Patents

Abstract

PURPOSE: Provided is a preparation method of an intermediate compound (chemical formula XI) for ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-3(s)-(1- hydroxyprop-2-ylamino)acrylate (chemical formula I), a precursor for Levofloxacin, an antibacterial drug. The drug is produced by using the above intermediate in high yield and this method is useful industrially. CONSTITUTION: The process comprises reacting 2,3,4,5-tetrafluorobenzoylchloride (chemical formula II) with ethyl 3-(dimethylamino)acrylate (chemical formula III) in a solvent or mixed solvent selected from DMSO, DMF, CH3CON(CH3)2, CH3CN, ETOOCH3 at -5 -100deg.C to make racemic form of ethyl 2-2-(2,3,4,5-tetrafluorobenzoyl)-3-(1- hydroxyprop-2-ylamino) acrylate (chemical formula XI) and reacting this compound, isolated or as reaction mixture, with (S)-(+)-2-amino-1-propanol (chemical formula IV), which is a reduction product of L-alanine, at 0-100deg.C in water, ethanolic solvent or their mixture.

Description

Process for producing ethyl 2- (2,3,4,5-tetrafluorobenzoyl) -3 (S)-(1-hydroxyprop-2-ylamino) acrylate and intermediate compounds thereof ethyl 2- (2,3,4,5-tetrafluorobenzoyl) -3 (S)-(1-hydroxyprop-2-ylamino) acrylate and intermediate compound

The present invention provides a process for preparing ethyl 2- (2,3,4,5-tetrafluorobenzoyl) -3 (S)-(1-hydroxyprop-2-ylamino) acrylate and novel intermediate compounds thereof It is about.

Ethyl 2- (2,3,4,5-tetrafluorobenzoyl) -3 (S)-(1-hydroxyprop-2-ylamino) acrylate is a compound (-)-9- useful as an antimicrobial agent. fluoro-2,3-dihydro -3 (S) - methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7 H - pyrido

It is used as an intermediate to prepare [1,2,3-dec] -1,4-benzoxazine-6-carboxylic acid, also known as Levofloxacin.

Chem. Pharm. Bull., Vol. 34, 4098-4102 (1986) are prepared by reacting ethyl 2,3,4,5-tetrafluorobenzoyl acetate of formula (V) with triethylol phosphomate of formula (VI), as represented by the following scheme. An acrylate derivative of formula (VII) was produced and then reacted with 2-amino-1-propanol of formula (VIII), which is a racemate without separation, to give an ethyltrile of formula (IX) as a racemate without optical activity. It is described that (2,3,4,5-tetrafluorobenzoyl) -3- (1-hydroxyprop-2-ylamino) acrylate can be obtained in a yield of 74%:

However, the main disadvantage of the known method is that the preparation of the acrylate derivative of formula (VII), which is a reaction intermediate, requires a very high reaction temperature condition of 140 ° C. or higher, and the compound of formula (V) which is a starting material as shown in the following scheme. In order to obtain Ethylene Magnesium Malonate of the general formula (X) which is very sensitive to moisture, the reaction route is long and inefficient, which is inappropriate for industrial application because it has to be prepared directly using a highly flammable solvent such as ether or tetrahydrofuran. Do:

In addition, since the compound of formula (XI) obtained by reacting the compound of formula (VII) with 2-amino-1-propanol of formula (VIII), which is a racemate, has no optical activity, it is necessary to study the separation process. Even if there is a disadvantage that the yield is bound to be less than half.

The present inventors have studied to solve the problems of the above known method for preparing ethyl 2- (2,3,4,5-tetrafluorobenzoyl) -3- (1-hydroxyprop-2-ylamino) acrylate. Ethyl 2- (2,3,4,5-tetrafluorobenzoyl)

A novel method has been found that allows the preparation of -3 (S)-(1-hydroxyprop-2-ylamino) acrylate in a simple and high yield.

The present invention is characterized by reacting a compound of formula (XI) with (S)-(+)-2-amino-1-propanol of formula (IV) Provided is a process for preparing 3,4,5-tetrafluorobenzoyl) -3 (S)-(1-hydroxyprop-2-ylamino) acrylate:

The reaction of the compound of formula (XI) according to the invention with (S)-(+)-2-amino-1-propanol is carried out at 0 ° C to 100 ° C, preferably 10 ° C to 30 ° C in a protic polar solvent, 1 to 10 hours, preferably 2 to 3 hours. Examples of protic polar solvents include water, ethanol solvents or mixtures of these solvents.

Compounds of formula (XI) are produced according to the invention by reacting 2,3,4,5-tetrafluorobenzoyl chloride of formula (II) with ethyl 3- (dimethylamino) acrylate of formula (III) :

The reaction of 2,3,4,5-tetrafluorobenzoyl chloride and ethyl 3- (dimethylamino) acrylate according to the present invention is carried out at -5 ° C to 100 ° C, preferably 0 ° C to 20 ° C, in a polar solvent. Under temperature, 2 hours to 50 hours, preferably 12 hours to 15 hours. Examples of polar solvents include dimethyl sulfoxide, dimethylformamide, dimethylacetamide, acetonitrile, ethyl acetate or mixtures of two or more thereof.

In another aspect, the present invention provides novel compounds of formula (XI), which are intermediates.

In the process of the present invention, the compound of formula (XI) is produced by reacting 2,3,4,5-tetrafluorobenzoyl chloride with ethyl 3- (dimethylamino) acrylate and then separated (S)-( Reaction with (S)-(+)-2-amino-1-propanol directly in situ without reacting or separating with +)-2-amino-1-propanol to give the desired ethyl 2- (2,3,4 , 5-tetrafluorobenzoyl) -3 (S)-(1-hydroxyprop-2-ylamino) acrylate can be produced.

2,3,4,5, -tetrafluorobenzoyl chloride of formula (II) used in the process of the present invention is a known compound 2,3,4,5- of formula (XII) Tetrafluorobenzoic acid [see Chem. Pharm. Bull., Vol. 34, 4098-4102 (1986) can be readily prepared:

In addition, compounds of formula (IV) with optical activity can be readily prepared by reducing L-alanine of cheap formula (XIII), which is readily available from nature:

As the reducing agent, lithium aluminum hydride, boron trifluoride, Raney nickel, sodium borohydride, or the like may be used.

The following examples illustrate the invention. However, these examples do not limit the scope of the present invention.

Example 1

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

3.5 L of tetrahydrofuran was put into a 1 L reaction part, and the temperature of the reaction part was cooled to 0 degreeC under nitrogen stream. Lithium aluminum hydride 75.9g (2 mole) was added to this reaction part, and it stirred for 30 minutes, and it was made to turbid. Then, L-alanine 89.1g (1 mole) was added to the reaction part by keeping it at 10 degrees C or less, and the reaction mixture liquid for 24 hours. It was stirred at reflux. After the reaction was completed, the reaction unit was cooled to 0 ° C., and 360 mL of purified water and 90 mL of 15% aqueous sodium hydroxide solution were gradually added thereto, stirred at 18 to 22 ° C. for 3 hours, and the precipitate was filtered off. The filtrate was dried and filtered through magnesium sulfate and concentrated under reduced pressure 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, = CH CH ₃ ), 2.79 (1H, m, -OH),

2.98 (1H, m, = CH CH 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 2,3,4,5-tetrafluorobenzoyl chloride

After replacing the 1 L reaction part with nitrogen with air, thionyl chloride 306.6 g (2.5 mole) and N, N′ -dimethylformamide 7.3 g (0.1 mole) were sequentially added and stirred at room temperature for 30 minutes. After 194.1 g (1 mole) of 2,3,4,5-tetrafluorobenzoic acid was slowly added to the reaction mixture, the temperature of the reaction portion was warmed to 95 ° C. and stirred for 15 hours. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure and residual thionyl chloride was removed to obtain 204.0 g (96%) of 2,3,4,5-tetrafluorobenzoyl chloride.

H ¹ NMR (CDCl ₃ , 300 MHz) (ppm):

7.7329-7.96 (1H, aromatic H)

Example 3

Preparation of Compounds of Formula (XI)

1.5L of acetonitrile was added to the 3L reaction section, and 143.2g (1 mole) of ethyl 3- (dimethylamino) acrylate was completely dissolved. 206.5g (2 mole) of triethylamine was added thereto, and the temperature of the reaction section was cooled to 0 ° C. Stir for 30 minutes. To this reaction mixture, a solution obtained by diluting 212.53 g (1 mole) of 2,3,4,5-tetrafluorobenzoyl chloride in 500 mL of acetonitrile was added and stirred while maintaining the temperature of the reaction section at 10 ° C or lower. The temperature of the reaction portion was adjusted to 10 ° C. and stirred for 14 hours. After the reaction was completed, the reaction unit was cooled to 0 ° C., the precipitate was filtered off, and the filtrate was concentrated under reduced pressure to remove the solvent to obtain the title compound.

IR: υ _max (cm ^-1 ): 1,693, 1,657, 1,597, 1,553, 1,248, 1,021

H ¹ NMR (CDCl ₃ , 300 MHz) (ppm):

0.95 (3H, t, CO ₂ CH ₂ CH ₃ )

3.05 and 3.40 [6H, respectively br, —N (CH ₃ ) ₂ ]

3.82 (2H, q, -CO ₂ CH ₂ CH ₃ )

6.78-6.95 (1H, m, aromatic H)

8.03 [1H, s, -CHN (CH ₃ ) ₂ ]

Example 4

Preparation of ethyl 2- (2,3,4,5-tetrafluorobenzoyl) -3 (S)-(1-hydroxyprop-2-ylamino) acrylate

The compound obtained in Example 3 was dissolved in 1.5 L of ethanol and completely dissolved, and then cooled to 0 ° C. and stirred for 30 minutes. A solution obtained by diluting 112.7 g (1.5 mole) of (S)-(+)-2-amino-1-propanol in 500 mL of ethanol was added to this reaction part while maintaining the temperature of the reaction part at 10 ° C. or lower, and then 18 to 22 ° C. Stirred for 3 hours. After completion of the reaction, the solvent was concentrated under reduced pressure. 1L of toluene was added to the reaction concentrate to completely dissolve it, and 1L of purified water was added thereto, washed twice, and the organic layer was separated. The organic layer was washed again with 1 L of 10% aqueous sodium bicarbonate solution, and the organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 342.3 g (98%) of ethyl 2- (2,3,4,5-tetrafluoro). Benzoyl) -3 (S)-(1-hydroxyprop-2-ylamino) acrylate was obtained.

IR: υ _max (cm ^-1 ): 3490, 1682, 1628

H ¹ NMR (CDCl ₃ , 300 MHz) (ppm):

0.97 and 1.11 (3H, t, -OCH ₂ CH ₃ ),

1.35 and 1.38 (3H, d, -NHCH CH ₃ ), respectively

1.80-1.94 (1H, br, -OH), 3.42 -3.84 (3H, m, = N CHCH ₂ O-),

4.03 and 4.07 (2H, q, -O CH ₂ CH ₃ ),

6.80 to 7.03 (1H, m, aromatic H),

9.10 to 9.65 and 11.30 to 12.53 (1H, br respectively = NH)

[α] _D = -72.5。 (c = 0.15, CHCl ₃ )

The process of the present invention provides high yield of ethyl 2- (2,3,4,5-tetrafluorobenzoyl) -3 (S)-(1-hydroxyprop-2-ylamino) acrylate in a simple process. It is very useful industrially.

Claims (9)

A compound of formula (XI) is reacted with (S)-(+)-2-amino-1-propanol of formula (IV) to yield ethyl 2- (2,3, Process for preparing 4,5-tetrafluorobenzoyl) -3 (S)-(1-hydroxyprop-2-ylamino) acrylate: The process of claim 1 wherein the reaction is carried out in water, an ethanol solvent or a mixture of these solvents. The process of claim 2 wherein the reaction is carried out at a temperature of 0 ° C. to 100 ° C. 4. The method of claim 1, wherein (S)-(+)-2-amino-1-propanol of formula (IV) is produced by reducing L-alanine. The process according to claim 4, wherein lithium aluminum hydride, boron trifluoride, Raney nickel or sodium borohydride are used as the reducing agent. A compound of formula (XI) A compound of formula (XI) according to claim 6 is reacted by reacting 2,3,4,5-tetrafluorobenzoyl chloride of formula (II) with ethyl 3- (dimethylamino) acrylate of formula (III) How to manufacture: 8. The process according to claim 7, wherein the reaction is carried out in dimethylsulfoxide, dimethylformamide, dimethylacetamide, acetonitrile, ethyl acetate or a mixture of two or more thereof. The process of claim 8, wherein the reaction is carried out at temperatures between −5 ° C. and 100 ° C. 10.