KR100403143B1 - A manufacturing method of 1-bromoethyl acetate - Google Patents

Abstract

The present invention relates to a method for preparing 1-bromoethyl acetate, and provides a method for preparing 1-bromoethyl acetate by reacting acetyl bromide with paraaldehyde.

Description

A manufacturing method of 1-bromoethyl acetate

The present invention relates to a process which can produce 1-bromoethyl acetate in high industrial convenience.

1-Bromoethyl acetate represented by the following Chemical Formula 1 is an ester of an organic acid of 4-position of acetoxyethyl group in the case of cepuroxime axetyl developed to increase the oral absorption of cepuroxime, a broad-spectrum cephatic antibiotic for injection. It is introduced.

Such 1-bromoethyl acetate is generally prepared by reacting acetaldehyde and acetyl bromide under a zinc chloride catalyst, and the scheme is as follows (see British Patent No. 1,571,683).

However, acetaldehyde used in this method is an irritating combustible gas having a low boiling point (21 ° C.), which is difficult to industrially use, store, and transport, and has a constant reaction in the reactor to prevent evaporation of acetaldehyde during the reaction. The pressure must be maintained and the purification process of fractional distillation not industrially easy to separate pure 1-bromoethyl acetate.

The distillation of distillation is a technique of high industrial difficulty as a technique of separating using a boiling point difference of a substance to separate only a desired object from a solution in which various substances are mixed. In addition, acetyl bromide remains because the fractionation distillation makes it difficult to obtain the target product in a pure state. Such remaining acetyl bromide is a decisive cause of side reactions during the preparation of cefuroxime acetil in the next step. Therefore, the technique of producing 1-bromoethyl acetate in high purity is very important for the research in this field and is an important factor in determining the efficiency of the reaction and the purity of the final product.

In order to solve this problem, Korean Patent Publication Nos. 2000-15621 and 1999-6489 disclose a method of preparing 1-bromoethyl acetate using vinyl acetate and hydrobromic acid as in Scheme 2 below. Although described, there are disadvantages of industrial separation because of the use of toxic gas hydrobromic acid.

Therefore, the technical problem to be achieved by the present invention is to provide a method for producing high-purity 1-bromoethyl acetate using a raw material which is easy to use industrially and undergoes a simple purification process.

In order to achieve the above technical problem, the present invention provides a method for producing 1-bromoethyl acetate, which is prepared by reacting acetyl bromide and paraaldehyde.

In the production method according to the present invention, the paraaldehyde is preferably used in an amount of 0.8 to 1.5 equivalents, more preferably 1 equivalent.

In the production method according to the invention, the reaction is preferably carried out under a zinc chloride catalyst.

In the production method according to the invention, the temperature during the reaction is preferably 30 to 50 ° C, more preferably 40 ° C.

In addition, the manufacturing method according to the present invention may further comprise the step of washing by removing the acidic substances such as unreacted acetyl bromide and HBr with water and distillation under reduced pressure to separate the pure 1-bromoethyl acetate.

Method for preparing 1-bromoethyl acetate according to the present invention as described above using a high boiling point (123 to 124 ℃) instead of the conventional acetaldehyde (paradealdehyde) that is easy to use industrially, storage, transport, etc. There is an advantage in that it can be reacted without pressure in the reactor, which is convenient and safe, and when using conventional acetaldehyde, an excess of acetaldehyde should be used because of volatility, but in the present invention, there is no volatility problem, and thus only a small amount is used. Preferably, 0.8 to 1.5 equivalents, more preferably only 1 equivalent may be used.

In addition, to separate pure 1-bromoethyl acetate has the advantage that can be purified simply by high-purity by washing with water and vacuum distillation without fractional distillation process.

Hereinafter, the manufacturing method according to the present invention will be described in detail.

First, 1-bromoethyl acetate is prepared by reacting 0.8 to 1.5 equivalents of paraaldehyde, preferably 1 equivalent, if necessary, under a zinc chloride catalyst to 1 equivalent of acetyl bromide. The reaction scheme of the preparation method according to the present invention is as follows.

In the above reaction, the amount of zinc chloride used as the catalyst is not particularly limited, but it is preferable to use 0.002 equivalents to 0.004 equivalents.

In addition, the temperature during the reaction is preferably maintained at 30 to 50 ℃, more preferably it is most efficient to react for 2 to 3 hours at a temperature of 40 ℃, there is no need to use a separate solvent.

In order to obtain the desired product after completion of the reaction, unreacted acidic substances such as acetyl bromide and HBr were removed with an aqueous layer using water such as methylene chloride and distilled water, and only pure 1-bromoethyl acetate was extracted and separated into an organic layer.

The organic layer separated as described above can be distilled under reduced pressure to obtain high purity 1-bromoethyl acetate as a liquid substance. The 1-bromoethyl acetate thus prepared is used as a raw material for the preparation of cefuroxime acetyl without further purification. Can be used.

When preparing 1-bromoethyl acetate by the method according to the present invention as described above can be obtained in a yield of 90% or more, can be prepared in a purity of 95% or more by gas chromatography and nuclear magnetic resonance spectra. It was confirmed.

In addition, in the case of producing cefuroxime acetyl using 1-bromoethyl acetate prepared from the present invention, purity of 99.5% or more, R / S isomer ratio of 0.495 to 0.535, and impurity delta-2 isomer of 0.1% or less, It has been confirmed that the anti-isomer can produce high purity crystalline cefuroxime axetyl of 0.1% or less.

Hereinafter, the present invention will be described in detail by way of examples, but the scope of the present invention is not limited thereto.

Example 1

66.3 g of acetyl bromide and 0.27 g of zinc chloride were added to a 250 ml three-necked flask, and 23.7 g of paraaldehyde was added with proper stirring. The reaction was terminated after stirring at 40 ° C. for 2 hours. Then methylene chloride and distilled water were added and stirred to wash unreacted acetyl bromide and impurities. Next, the layers are separated, the organic layer is taken, dried over anhydrous sodium sulfate, and filtered under reduced pressure. After filtration under reduced pressure, the filtrate was concentrated to give clear 1-bromoethyl acetate.

Yield: 90.7%

Quality: above 95% (GC), specific gravity 1.44

NMR (CDCl 3, δ ppm): 6.67 (q, 1H), 2.1 (s, 3H), 2.0 (d, 3H)

<Preparation Example 1 of Sepuroxime Axetyl>

604 ml of dimethyl acetamide and 120.8 g of cefuroxime sodium were added to a 1 L flask, and 68 g of 1-bromoethyl acetate obtained in Example 1 was added under ice cooling, followed by stirring for 4 hours. An aqueous sodium bicarbonate solution and ethyl acetate were then added and stirred for 1 hour. Next, the layers are separated and the organic layer is washed several times with a saturated aqueous sodium chloride solution. The extract is concentrated under reduced pressure and the target product is crystallized with a mixed solvent of isopropanol and nucleic acid. Filtration under reduced pressure afforded the crystalline cefuroxime axetyl target.

Yield: 85%

Quality: above 99.5% purity, R / S isomer ratio is 0.495 ~ 0.535,

Delta-2 isomer is 0.1% or less, Anti isomer is 0.1% or less

As described above, the method for preparing 1-bromoethyl acetate according to the present invention can easily obtain the target compound in high purity industrially using paraaldehyde, and in particular, the obtained target product is purified without cepuroxime axetyl. It is a useful manufacturing method that can be used to prepare the.

Claims (5)

A process for preparing 1-bromoethyl acetate, which is prepared by reacting acetyl bromide with paraaldehyde under a catalyst of zinc chloride. The method for preparing 1-bromoethyl acetate according to claim 1, wherein 0.8 to 1.5 equivalents of paraaldehyde are used. The method of claim 1, wherein the reaction temperature is 30 to 50 ℃. delete [Claim 2] The 1-bromo according to claim 1, further comprising washing HBr generated in the reaction with unreacted acetyl bromide with water and distilling under reduced pressure to separate pure 1-bromoethyl acetate. Process for the preparation of ethyl acetate.