JP2000053661A - Production of 3-(2-bromopropionyl)-2-oxazolidinone derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject 3-(2-bromopropionyl)-2-oxazolidinone derivative of high purity that is useful for production of β-lactam antibiotics in high yield by trimethylsilylating a specific oxazolidinone derivative with a specific compound in a prescribed amount of an organic solvent before removal of by- products and reaction with a halide, then subjecting the product to a specific after treatment. SOLUTION: (A) A compound of formula I (R1-R4 are each a 1-4C alkyl or the like), for example, 4,4-dimethyl-2-oxazolidinone or the like is trimethylsilylated with chlorotrimethylsilane and a tertiary amine in (B) an organic solvent at a mass ratio A/(A+B) of <=0.15, then the amine hydrochloride as a by-product is removed. Subsequently, a 2-bromopropionyl halide is allowed to react with the remaining product and altertreated by adjusting the reaction mixture in its pH to 5.0-7.0, separating the aqueous layer. The component B is distilled off at a temperature lower than 70 deg.C under reduced pressure to collect the objective compound, for example, 3-(2-bromo-propionyl)-4,4-dimethyl-2- oxazolidinone or the like.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an improved method for producing a 3- (2-bromopropionyl) -2-oxazolidinone derivative.

[0002]

BACKGROUND OF THE INVENTION 3- (2-Bromopropionyl) -2-
Oxazolidinone derivatives are important compounds as raw materials for producing β-lactam antibiotics (Tetrahedron Letters, Vol. 28, p. 6625, p. 6629 (1987).
Year), JP-A-63-10765). As a method for producing a 3- (2-bromopropionyl) -2-oxazolidinone derivative, the corresponding 2-oxazolidinone derivative is trimethylsilylated using chlorotrimethylsilane and a tertiary amine, and then a by-product amine hydrochloride is produced. There is known a method of removing and then reacting with 2-bromopropionyl halide (JP-A-2-262568).

[0003]

According to this method, the desired compound can be obtained in a high yield under relatively mild conditions with few by-products, but it is not sufficient in terms of purity and yield. It was not satisfactory. The purpose of the present invention is
It is an object of the present invention to provide a method for producing a 3- (2-bromopropionyl) -2-oxazolidinone derivative that can always produce a 3- (2-bromopropionyl) -2-oxazolidinone derivative with high yield and high purity.

[0004]

Means for Solving the Problems The present inventors have found that 3- (2
(Bromopropionyl) -2-oxazolidinone derivative has been studied intensively so that it can always be produced with high yield and high purity. If the ratio (m / M) to the total mass M of the organic solvent (m / M) is 0.15 or less, the reaction is allowed to proceed under sufficient stirring even if tertiary amine hydrochloride is gradually generated in the first trimethylsilylation reaction. (2) After the reaction with 2-bromopropionyl halide, an alkaline aqueous solution was added to adjust the pH to 5.0 to 7.0.
If the aqueous layer is separated as 0, hexamethylsiloxane and hydrochloric acid derived from excess chlorotrimethylsilane and 2-bromopropionic acid and hydrogen bromide derived from excess 2-bromopropionyl halide are used in excess. The 2-oxazolidinone derivative and the like in the reaction can be removed from the aqueous layer, and 3- (2-bromopropionyl)-having high purity can be obtained.
(2) that a 2-oxazolidinone derivative can be produced;
-After work-up of the bromopropionyl halide reaction mixture,
When the organic solvent used in the reaction, particularly the organic solvent is a halogenated hydrocarbon, the 3- (2-bromopropionyl) -2-oxazolidinone derivative having a high purity can be obtained by distilling off the solvent under reduced pressure at 70 ° C. or lower. They have found that they can be produced in good yield and have completed the present invention.

That is, the production method of the present invention comprises a compound represented by the general formula (I):

Embedded image(Where R₁~ R_FourAre the same or different C₁~ C_FourNo
Represents a alkyl, phenyl, benzyl or hydrogen atom.
Suka, R₁And R_TwoBut together C_Two~ C_FiveAlkyre
, And simultaneously or separately_ThreeAnd R_FourTogether
Become C_Two~ C _FiveRepresents an alkylene chain. )
2-oxazolidinone derivative in an organic solvent
Trimethylation using trimethylsilane and tertiary amines
After the lusilylation, the by-product amine hydrochloride is removed, and
Reaction with 2-bromopropionyl halide
Formula (II):

Embedded image (Wherein, R _{1 to} R ₄ are the same as the groups described above.) In the method for producing a 3- (2-bromopropionyl) -2-oxazolidinone derivative represented by the formula (1), the trimethylsilylation is The mass m of the 2-oxazolidinone derivative represented by the general formula (I) and the total mass M of the 2-oxazolidinone derivative represented by the general formula (I) and an organic solvent
And the ratio (m / M) is 0.15 or less,
(2) After the reaction with the 2-bromopropionyl halide, an alkaline aqueous solution is added to adjust the pH to 5.0 to 7.0,
Then, a post-treatment for separating the aqueous layer is performed. (3) After the post-treatment, the organic solvent used for the reaction is distilled off under reduced pressure at a temperature of 70 ° C. or less.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION The 2-oxazolidinone derivatives used in the present invention include 2-oxazolidinone,
4-dimethyl-2-oxazolidinone, 4-methyl-5
-Propyl-2-oxazolidinone, 4-isopropyl-2-oxazolidinone, 4-benzyl-2-oxazolidinone, 4-phenyl-2-oxazolidinone, 4,
Examples thereof include, but are not limited to, 4-dibutyl-5,5-pentamethylene-2-oxazolidinone.

The tertiary amines used in the present invention include, for example, lower alkylamines such as triethylamine, tripropylamine, tributylamine and diisopropylethylamine, and pyridine. The amounts of the trimethylchlorosilane and the tertiary amines used are 2
Each oxazolidinone derivative is used in an amount of about 1 equivalent or more, and usually about 1 to 1.5 equivalents, preferably about 1.1 to 1.3 equivalents, per equivalent.

The organic solvent used in the trimethylsilylation reaction in the present invention is preferably a solvent which does not easily dissolve tertiary amine hydrochloride by-produced in the reaction.
Examples thereof include 2-dichloroethane, carbon tetrachloride, tetrahydrofuran, chlorobenzene, ethyl acetate, and toluene. The amount of the organic solvent used is such that the ratio (m / M) of the mass m of the 2-oxazolidinone derivative to the total mass M of the 2-oxazolidinone derivative and the organic solvent is 0.15 or less, preferably 0.10 or less. is there. As a result, even if tertiary amine hydrochloride is gradually generated and precipitated in the first trimethylsilylation reaction, the reaction can be allowed to proceed with sufficient stirring. On the other hand, when the ratio (m / M) exceeds 0.15, stirring is hindered by the precipitated amine hydrochloride, and the reaction does not proceed smoothly. On the other hand, if the mass ratio is too small, the production amount of the 3- (2-bromopropionyl) -2-oxazolidinone derivative per reactor decreases, and the production cost increases. Is from about 0.02 to 0.15, preferably from about 0.
It is good to be in the range of 0.5 to 0.10.

[0009] The trimethylsilylation reaction is generally carried out at about -1.
It is carried out at a temperature of 0 to 60C, preferably about 10 to 40C. After the completion of the trimethylsilylation reaction, the by-product tertiary amine hydrochloride is removed. Normally, tertiary amine hydrochloride precipitates, and is removed by filtration means such as vacuum filtration and pressure filtration. Next, 2-bromopropionylation is performed by reacting with 2-bromopropionyl halide. 2
Examples of -bromopropionyl halide include 2-bromopropionyl bromide and 2-bromopropionyl chloride, and preferably, 2-bromopropionyl bromide is used. The amount of 2-bromopropionyl halide used is the 2-oxazolidinone derivative (I)
Usually, about 1 equivalent or more is used, preferably about 1.05 to 1.25 equivalent is used for 1 equivalent of the above. Also,
The reaction temperature for 2-bromopropionylation generally ranges from about 0 to
70 ° C, preferably 10 to 40 ° C. The solvent for the 2-bromopropionylation reaction is preferably the same organic solvent as the silylation reaction since the reaction is performed subsequent to the silylation reaction, but a different solvent from the silylation reaction is used. Can also. In each case, 2-
Since a liquid separation operation is performed as a post-treatment of the bromopropionylation reaction, a water-immiscible hydrophobic solvent is used as a solvent to be used.

After the 2-oxazolidinone derivative is trimethylsilylated using chlorotrimethylsilane and tertiary amines, the by-product amine hydrochloride is removed.
-Bromopropionyl halide is reacted to give 3- (2-
(Bromopropionyl) -2-oxazolidinone derivative is produced. After reacting with 2-bromopropionyl halide,
After adding water to separate the aqueous layer, an aqueous alkaline solution is added to adjust the pH to 5.0 to 7.0, preferably 6.0 to 6.5. This is because the 2-bromopropionyl halide used in a slight excess is hydrolyzed to 2-bromopropionic acid by adding water after the reaction, and the neutralization point of 2-bromopropionic acid is around pH 4.5. And the product 3- (2-bromopropionyl) -2-
This is because oxazolidinone derivatives are unstable under alkaline conditions. Therefore, when the pH is less than 5.0, 2-bromopropionic acid, which is an impurity, is not completely neutralized, and thus may remain in the organic layer and not migrate to the aqueous layer. On the other hand, when the pH exceeds 7.0, the resulting 3- (2-bromopropionyl) -2-oxazolidinone derivative becomes unstable because it becomes alkaline,
There is a risk of decomposition. Examples of the alkaline aqueous solution include aqueous solutions of sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, calcium carbonate, and the like.

After washing with stirring by adding an aqueous alkali solution, the aqueous layer is separated and the organic layer is further washed with water. By such treatment, in addition to 2-bromopropionic acid, hexamethyldisiloxane derived from chlorotrimethylsilane used in a slightly excessive amount, and the starting compound 2-oxazolidinone derivative can be removed to the aqueous layer side, The purity of the product 3- (2-bromopropionyl) -2-oxazolidinone derivative will be improved. The washing temperature with the alkaline aqueous solution is selected from the range of 0 ° C to 40 ° C, preferably 25 ° C to 30 ° C. The washing time with the alkaline aqueous solution varies depending on the amount of the reactants, washing temperature and the like, but is selected from the range of 0.1 to 24 hours.

After the post-treatment of the 2-bromopropionylation reaction, the organic solvent used in the reaction is concentrated. Concentration temperature is 70
C. or lower, preferably 50 ° C. or lower, and the organic solvent is concentrated under reduced pressure within this temperature range. When the temperature is higher than this temperature, the reactivity of the bromine atom of the 3- (2-bromopropionyl) -2-oxazolidinone derivative is high. Therefore, when the organic solvent is a halogenated hydrocarbon, the product 3- (2- Part of the bromopropionyl) -2-oxazolidinone derivative is 3- (2-chloropropionyl) -2
-It may be converted to oxazolidinone and the purity of the product may be reduced.

When the organic solvent is concentrated under reduced pressure, a 3- (2-bromopropionyl) -2-oxazolidinone derivative as a target compound can be obtained. The obtained 3- (2
The -bromopropionyl) -2-oxazolidinone derivative may be used as it is, or may be further purified, if necessary, by means such as recrystallization or chromatography.

【Example】

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to the following examples. Example 1 46.1 g (0.40 mol) of 4,4-dimethyl-2-oxazolidinone and 52.2 g of chlorotrimethylsilane were placed in a glass reactor equipped with a reflux condenser, a thermometer, a stirrer and a dropping funnel. (0.48 mol) and 500 g of 1,2-dichloroethane were charged (4,4-dimethyl-
Mass of 2-oxazolidinone and 4,4-dimethyl-2-
The ratio to the total mass of oxazolidinone and 1,2-dichloroethane is 0.08). Next, 48.6 g (0.48 mol) of triethylamine was added dropwise with stirring at a temperature of 20 to 30 ° C. over 1 hour. After the completion of the dropwise addition, the reaction was carried out at the same temperature for 1 hour. Then, the precipitated triethylamine hydrochloride was removed by filtration under reduced pressure. Add a small amount of 1,2-
Washed with dichloroethane. The filtrate and the washing solution were combined, charged into the same reactor as above, and 103.6 g (0.48 mol) of 2-bromopropionyl bromide was added dropwise thereto at 30 to 35 ° C over 1 hour with stirring. After the completion of the dropwise addition, the reaction was carried out at the same temperature for 1 hour.

After the completion of the reaction, 200 g of water was added to the reaction solution at the same temperature as at the time of the reaction, stirred, and then separated. Water 4 for organic layer
0 g and then 54.2% aqueous sodium bicarbonate solution (64.2 g) were added to adjust the pH of the aqueous layer to 6.2, followed by liquid separation. Further, the organic layer was washed with 80 g of water and separated. After such post-treatment, the solvent was reduced to 50 ° C under reduced pressure.
Was distilled off. Then, hexane was added to the residue for crystallization, and the precipitated crystals were collected by filtration under reduced pressure, rinsed with 75 g of hexane, dried and washed with 3- (2-bromopropionyl)-.
92.3 g of 4,4-dimethyl-2-oxazolidinone
(Purity 99.5%, yield 91.8%).

Comparative Example 1 In a glass reactor equipped with a reflux condenser, a thermometer, a stirrer, and a dropping funnel, 46.1 g (0.40 mol) of 4,4-dimethyl-2-oxazolidinone and chlorotrimethylsilane were added. 52.2 g (0.48 mol) and 184 g of 1,2-dichloroethane were charged (4,4-dimethyl-2-
The ratio of the mass of oxazolidinone to the total mass of 4,4-dimethyl-2-oxazolidinone and 1,2-dichloroethane is 0.2). Under stirring, triethylamine 4
When 8.6 g (0.48 mol) was added dropwise over 1 hour at a temperature of 20 to 30 ° C., it was difficult to stir the liquid uniformly due to the precipitated triethylamine hydrochloride, so that the reaction could be completed. Did not.

Comparative Example 2 After the reaction was carried out in the same manner as in Example 1, 200 g of water was added to the reaction solution at the same temperature as the reaction, the mixture was stirred, and then separated. 40 g of water and then 5% aqueous sodium bicarbonate were added to the organic layer to adjust the pH of the aqueous layer to 8.5. When this liquid was held at 40 ° C. for 6 hours, 3- (2-bromopropionyl)-
The purity of 4,4-dimethyl-2-oxazolidinone by gas chromatography was reduced by about 0.8% per hour. That is, under alkaline conditions, the product 3
-(2-bromopropionyl) -4,4-dimethyl-2
-Oxazolidinone was unstable.

Comparative Example 3 After the reaction was carried out in the same manner as in Example 1, 200 g of water was added to the reaction solution at the same temperature as the reaction, stirred, and then separated. 40 g of water and then 64.2 g of 5% aqueous sodium bicarbonate were added to the organic layer to adjust the pH of the aqueous layer to 6.2, followed by liquid separation. Further, the organic layer was washed with 80 g of water and separated. This solution is heated at 80 ° C under normal pressure for 8 hours.
Concentrated for hours. As a result, 3- (2-bromopropionyl) -4,4-dimethyl-2-oxazolidinone was 0.1%.
Gas chromatography analysis revealed that 5% was converted to 3- (2-chloropropionyl) -4,4-dimethyl-2-oxazolidinone. That is, when the organic solvent used is 1,2-dichloroethane, the boiling point is 83 ° C., so that 3- (2-bromopropionyl) -4,
The 4-dimethyl-2-oxazolidinone solution was added under normal pressure to 80
Concentration at 3 ° C. gives 3- (2-bromopropionyl)-
The purity of 4,4-dimethyl-2-oxazolidinone decreased.

[0019]

According to the present invention, the amount of the solvent at the time of the reaction, the post-treatment after the reaction and the concentration of the solvent are carried out under predetermined conditions, whereby the desired compound 3- (2-bromopropionyl) -2- (2- (2-bromopropionyl) -2-) is obtained. There is an effect that the oxazolidinone derivative can be produced with high yield and high purity.

Claims (1)

[Claims] 1. A compound of the general formula (I):(Where R₁~ R_FourAre the same or different C₁~ C_FourNo
Represents a alkyl, phenyl, benzyl or hydrogen atom.
Suka, R₁And R_TwoBut together C_Two~ C_FiveAlkyre
, And simultaneously or separately_ThreeAnd R_FourTogether
Become C_Two~ C _FiveRepresents an alkylene chain. )
2-oxazolidinone derivative in an organic solvent
Trimethylation using trimethylsilane and tertiary amines
After the lusilylation, the by-product amine hydrochloride is removed, and
Reaction with 2-bromopropionyl halide
Formula (II):(Where R₁~ R_FourIs the same as defined above. )
3- (2-bromopropionyl) -2-oxazo
A method for producing a lydinone derivative, comprising:
Methylsilylation is represented by the general formula (I).
Represented by the mass m of the sazolidinone derivative and the general formula (I)
Total mass M of 2-oxazolidinone derivative and organic solvent
And the ratio (m / M) is 0.15 or less,
(2) After the reaction with the 2-bromopropionyl halide,
The pH is adjusted to 5.0 to 7.0 by adding a lukari aqueous solution,
Then, a post-treatment for separating the aqueous layer is performed. (3) After the post-treatment,
The organic solvent used is distilled off under reduced pressure at a temperature of 70 ° C. or less.
3- (2-bromopropionyl)-
A method for producing a 2-oxazolidinone derivative.