KR20000015621A - Process for preparing high purity 1-bromoethyl carboxylate - Google Patents

Abstract

PURPOSE: The 1-bromoethyl carboxylate is prepared to high purity which has high converting rate and a good industrial utilization. CONSTITUTION: 1 Equivalent weight of vinyl carboxylates(formula II; R is methyl or tert-butyl group) are reacted with 0.5- 1.5 equivalent weight of hydrogen bromide gas at -78- 50 degree C to give 1-bromoethyl carboxylate(formula I). Thus, 425 g of hydrogen bromide gas obtained from PBr3 and H2O is added in 431 g of vinyl acetate at -10 degree C for 2 hours, left at room temperature for 2 hours. Obtained compound is distilled at 40 degree C, depressurized to give 836 g of title compound.

Description

New preparation method of high purity 1-bromoethyl carboxylate

The present invention relates to a novel process for preparing 1-bromoethyl carboxylate of formula (1) which is useful for the preparation of prodrugs of cephalosporin-based antibiotics.

Formula 1

Wherein R represents a methyl or t-butyl group.

The carboxyethyl atom group protects the large polarity of the useful compounds and can significantly lower the polarity or increase the usefulness of the compounds. Therefore, the carboxyethyl atom group is particularly useful for the preparation of prodrugs of cephalosporin antibiotics and other organic compounds. It is often used to indicate a function. For example, in the case of cefuroxime acetyl, which was developed to enhance the oral absorption of cefuroxime, an injectable broad-wave cephatic antibiotic, acetoxyethyl group is introduced as an ester of 4-position of organic acid, and recently developed as a broad-spectrum antibiotic. In the case of ceftaloxime pentecsil, pivaloyloxyethyl group is introduced as an ester. In addition, Japanese Patent Laid-Open No. 94-062601 describes the use of an acetoxyethyl group in the preparation of an antiallergic drug.

A reagent commonly used to introduce such a carboxyethyl group is 1-bromoethyl carboxylate, and 1-chloroethyl carboxylate, 1,1-bisacetoxyethyl, and the like are sometimes used.

Generally 1-bromoethyl carboxylate can be obtained by reacting acetaldehyde with a suitable acyl bromide (see EP 1571683). However, the acetaldehyde used in this process is often present in coexistence with the polymer and the acyl bromide used together is a very sensitive material to moisture. Therefore, 1-bromoethyl carboxylate obtained by this method should be purified by vacuum fractional distillation or the like, but it is difficult to obtain it in a pure state. Especially, the remaining reactant acyl bromide is a decisive cause of side reaction in the next step reaction. do. Another method is to replace chlorine in 1-chloroethyl carboxylate with bromine, but there is a disadvantage in that the substitution reaction does not occur quantitatively and thus the efficiency of subsequent reactions is inferior. Prodrug preparation using low-purity 1-bromoethyl carboxylate is an obvious cause of impurity production and it is virtually impossible to obtain the desired product in high purity. Therefore, the technique of producing 1-bromoethyl carboxylate with high purity is very important in this field of study, and is an important factor in determining the efficiency of the reaction and the purity of the final product.

The present inventors conducted an intensive study to solve the above-mentioned disadvantages, and as a result, addition reaction of the vinyl carboxylate of formula (2) with hydrobromic acid gas easily yielded 1-bromoethyl carboxylate of formula (1). The present invention has been completed by discovering that it can be produced in high purity.

Formula 1

Wherein R represents a methyl or t-butyl group.

The present invention relates to a method for easily producing 1-bromoethyl carboxylate of formula (1) by reacting vinyl carboxylate of formula (2) with hydrobromic acid gas.

Formula 1

Formula 2

Wherein R represents a methyl or t-butyl group.

Hydrobromic acid (gas) reacts quickly and quantitatively with vinyl carboxylates, and any side reaction product (e.g., isomer 2-bromoethyl carboxylate) when analyzed by gas chromatography or nuclear magnetic resonance spectra. Did not generate. In addition, even if a small amount of the starting material vinyl carboxylate in the reaction mixture does not affect the next reaction at all, it is possible to easily prepare a prodrug compound of the desired purity. Hydrobromic acid (gas) may be purchased and used as a gaseous product, or may be prepared in a gaseous state by adding a certain amount of water to phosphorus tribromide, acetyl bromide, and the like. In this case, the amount of hydrobromic acid (gas) used may be 0.5 to 1.5 equivalents based on 1 equivalent of vinyl carboxylate of formula (2), preferably 0.95 to 1.05 equivalents. The reaction can be carried out usually between -78 ° C and 50 ° C without solvent, preferably between -20 ° C and 0 ° C. Hydrobromic acid (gas) is preferably immersed in the vinyl carboxylate and introduced through a glass tube, in which case it is possible to control the amount introduced by installing a control system in the middle. The progress of the reaction can be confirmed by gas chromatography or nuclear magnetic resonance spectra. When the reaction was completed, the vinyl carboxylate was converted into 1-bromoethyl carboxylate in its entirety, and the reaction solution analysis showed that the bromoethyl carboxylate of formula (1) was subjected to the following desired reaction. It indicates that it has sufficient purity so that it can be used as it is without treatment.

The following examples are provided to illustrate the method of the present invention in more detail, and these examples do not limit the scope of the present invention.

Example 1. Preparation of 1-bromoethyl acetate

431 g of vinyl acetate was cooled down to -10 ° C. Hydrobromic acid (gas) (425 g, 1.05 equiv) prepared by reacting PBr ₃ with H ₂ O with appropriate stirring was injected over 2 hours. The temperature of the reaction was maintained at -10 ° C or lower until the injection of hydrobromic acid (gas) was completed, and allowed to stand at room temperature for 2 hours after the injection was completed. The mixture was distilled under reduced pressure at a temperature of 40 ° C. to remove volatiles to give 836 g (100%) of the title compound as a colorless liquid (purity of the target product identified by gas chromatography was 99.6%, and the remaining impurities were starting materials). Vinyl acetate). The analytical sample can be obtained in a yield of about 95% (794 g) by fractionally distilling the target product under a high vacuum (5 mmHg) at a temperature of 30 to 35 ℃.

Boiling Point: 30-35 ℃ (4㎜Hg)

¹ H-NMR (CDCl ₃ ); 6.65 (q, 1H), 2.07 (s, 3H), 1.95 (d, 3H)

Example 2. Synthesis of 1-bromoethyl pivalate

384.5 g of vinyl pivalate was cooled to -10 deg. Hydrobromic acid (gas) (255 g, 1.05 equiv) was injected over 2 hours with appropriate stirring. The temperature of the reaction was maintained at −10 ° C. or lower until the injection of hydrobromic acid (gas) was completed, and allowed to stand at room temperature for 2 hours after the injection was completed. The mixture was distilled off at a temperature of 40 ° C. under reduced pressure to remove volatiles to give 608.5 g (yield: 97%) of the title compound as a colorless liquid.

¹ H-NMR (CDCl ₃ ); 6.60 (q, 1H), 1.95 (d, 3H), 1.25 (s, 9H)

Example 1 Preparation of Amorphous Sepuroxime Axetyl

10 g of cefuroxime sodium and 5 g of zinc iodide (Znl ₂ ) were added to 40 ml of dimethylacetamide, followed by stirring at 10 ° C. for 30 minutes. 3.6 ml of 1-bromoethyl acetate prepared in Example 1 was added thereto, followed by further stirring at the same temperature for 2 hours. The reaction mixture was poured into a mixture of 50 ml of saturated sodium bicarbonate water, 50 ml of saturated brine, and 100 ml of ethyl acetate, stirred vigorously for 30 minutes, and the organic layer was separated. The aqueous layer was further extracted with 50 ml of ethyl acetate to separate the organic layer and the organic layers thus obtained were combined. The obtained organic layer was washed successively with 40 ml of 2N hydrochloric acid and 60 ml of saturated brine. The organic solution was dried over anhydrous magnesium sulfate, decolorized by adding 2 g of activated carbon for 30 minutes, and filtered through celite. The resulting clear, colorless solution was distilled under reduced pressure, concentrated to 125 g, and dispersed in vigorous stirring in 900 ml of n-hexane. The solid obtained was filtered quickly and dried for 2 days with 40 ° C. hot air to yield 9.69 g (yield: 85%) of amorphous cefuroxime axetyl as a white solid.

Purity: 98.5% (HPLC)

Impurities: Delta-2 isomer (0.15%), Anti isomer (0.15%)

Isomer ratio of Sepuroxime Axetyl: 1: 1.03

The production method of the present invention can be converted to a whole amount of the vinyl carboxylate as a starting material to obtain the target compound in high purity, in particular, because the obtained target compound can be used in the next step without post-treatment, industrial availability is large.

Claims (3)

A process for producing 1-bromoethyl carboxylate of formula (1) by reacting vinyl carboxylate of formula (2) with hydrobromic acid gas. Formula 1 Formula 2 Wherein R represents a methyl or t-butyl group. The process according to claim 1, wherein 0.5 to 1.5 equivalents of hydrobromic acid gas are used per 1 equivalent of vinyl carboxylate of formula (2). The process of claim 1 wherein the reaction is carried out at a temperature of −78 ° C. to 50 ° C. 7.