DE10333080A1 - Production of acetoacetate esters for use as pharmaceutical intermediates, e.g. p-nitrobenzyl acetoacetate, involves reacting diketene with a benzyl alcohol in presence of a cyclic amine as catalyst - Google Patents

Abstract

Nitrogen-containing cyclic organic bases are used as catalysts in a method for the production of acetoacetic acid esters by reacting diketene with a benzyl alcohol in presence of a solvent.

Description

Background of the Invention

1. Field of the Invention

The present invention relates refer to a process for the preparation of acetoacetic acid esters, in particular for the production of acetoacetic acid benzyl esters. These compounds can be used, for example, as intermediate materials for pharmaceutical Intermediates and other fine chemicals.

2. Description of the related State of the art

Benzoacetoacetate, for example used as pharmaceutical intermediates. For example is p-Nitrobenzylacetoacetate useful in the pharmaceutical field Preparations as Intermediate for Carbapenem antibiotics. Conventional manufacturing processes of p-nitrobenzylacetoacetate for example (a) a process in which p-nitrobenzyl alcohol can react with diketene in ToIuol by means of catalysis Triethylamine (untested Japanese Patent Application Publication No. 03-197 459), (b) a Process in which p-nitrobenzyl alcohol with diketene in benzene lets react through Catalysis using p-toluenesulfonic acid (U.S. Patent No. 3,014,838), (c) a method using p-nitrobenzyl alcohol with ethyl acetoacetate in a molar ratio of 1: 1.08 in toluene can react (unexamined Japanese Patent Application Publication No. 61-275 284) and (d) a process with p-nitrobenzyl alcohol with an acetoacetic acid ester in a molar ratio from 1: 1.2 to 1: 50 in ToIuol (unexamined Japanese patent application publication No. 09-132 550).

The process (b) in which p-toluenesulfonic acid as Catalyst is used, however, gives a low yield of about 78%.

Pharmaceutical intermediates have to have a high purity with less impurities to a Avoid contamination with substances that are detrimental Influence on the effectiveness of the final pharmaceutical preparation can have. In the conventional manufacturing processes, however, one often occurs Contamination of the products due to contamination as this Procedures often side reactions cause and thereby large Amounts of by-products result. For example, the Process using triethylamine as a catalyst size Amounts of impurities and the products obtained are not suitable as starting materials for pharmaceutical preparations, although the products in higher Yields are obtained.

There is therefore a need for a method the acetoacetic acid ester can result in high purity, which contain fewer by-products and can be used as pharmaceutical intermediates.

Summary the invention

The aim of the present invention is it is therefore necessary to provide a process for the preparation of acetoacetic acid esters, the highly pure acetoacetic acid ester with fewer by-products.

After extensive investigations in an effort to achieve the above goal, the Inventors of the present invention found that when one Diketene with a benzyl alcohol in the presence of at least one solvent can react by catalysis with a specific catalyst that Side reactions are prevented and high purity acetoacetic acid esters can be obtained with fewer contaminants. The present invention is based on these findings.

Object of the present invention is in particular a process for the preparation of an acetoacetic acid ester, comprising the steps of: reacting diketene with a benzyl alcohol in the presence of a solvent by catalysis using at least one nitrogen-containing cyclic organic base, creating a corresponding acetoacetic acid ester is obtained. The nitrogen-containing cyclic organic base includes, for example, cyclic amines. The benzyl alcohol can be p-nitrobenzyl alcohol his. The solvent includes, for example, aromatic solvents.

With the production method according to the invention side reactions can be effectively suppressed and high purity acetoacetic acid esters with less contamination by impurities can be achieved by carrying out a reaction in the presence of at least one solvent carried out by catalysis using a nitrogen-containing cyclic organic base. The resulting acetoacetic acid esters can be used, for example, as pharmaceutical intermediates.

Other goals, features and advantages of the present invention will become apparent from the following description preferred embodiments out.

description of the preferred embodiments

Benzyl alcohols which can be used as starting material according to the invention include, for example, benzyl alcohol and benzyl alcohols, each of which has at least one substituent on its benzene ring or in the neighboring position to a hydroxyl group. These substituents include, for example, but are not limited to, halogen atoms; Alkoxy groups such as methoxy, ethoxy, isopropoxy and other C ₁ -C ₆ alkoxy groups; Acyl groups, for example acetyl, propionyl, butyryl, benzoyl and other C ₁ -C ₇ acyl groups; the carboxyl group; Alkoxycarbonyl groups, for example methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and other C ₁ -C ₆ alkoxycarbonyl groups; the amino group; Alkylamino groups, for example N-methylamino, N, N-dimethylamino and other mono- or di-C ₁ -C ₄ -alkylamino groups; the hydroxyl group; the mercapto group; substituted thio groups, for example alkylthio groups, cycloalkylthio groups and arylthio groups; substituted or unsubstituted carbamoyl groups; the cyano group; the nitro group; the sulfo group; Alkyl groups, for example methyl, ethyl, propyl, isopropyl and other C ₁ -C ₆ alkyl groups; Alkenyl groups, for example vinyl, propenyl and other C ₂ -C ₆ alkenyl groups; Alkynyl groups, for example ethynyl, propynyl and other C ₂ -C ₆ alkynyl groups; alicyclic hydrocarbon groups, eg cyclopentyl, cyclohexyl and other C ₃ -C ₈ cycloalkyl groups, and adamantyl and other bridging groups; aromatic hydrocarbon groups, for example phenyl, naphthyl and other aryl groups; and heterocyclic groups.

With benzyl alcohols you can Hydroxyl group may be substituted by a protecting group that removes or can be eliminated. To such protecting groups that removed can be belong for example methyl, ethyl, isopropyl, methoxymethyl, 1-methoxyethyl and ethoxymethyl groups and other groups containing an ether, acetal or can form a hemiacetal group with a hydroxyl group; acyl groups, Sulfonyl groups, alkoxycarbonyl groups, carbamoyl groups and others Groups by acids like carboxylic acids, sulfonic acids, Carbonic acid, carbamate, Sulfuric acid, phosphoric acid and boric acid Removal of the OH group are derived.

Examples of the benzyl alcohols include benzyl alcohol; o-nitrobenzyl alcohol, p-nitrobenzyl alcohol, salicyl alcohol, o-methylbenzyl alcohol, m-methylbenzyl alcohol, p-methylbenzyl alcohol, o-methoxybenzyl alcohol, m-methoxybenzyl alcohol, p-methoxybenzyl alcohol, o-chlorobenzyl alcohol, m-chlorobenzyl alcohol, p-chlorobenzyl alcohol, p-cyanobenzyl alcohol, p-acetylbenzyl alcohol, p-methoxycarbonylbenzyl alcohol and others Benzyl alcohols, each with a substituent (a nitro, cyano, Acyl, alkoxycarbonyl group, halogen atoms and other electrons attractive groups or alkoxy, alkyl, hydroxyl and other electrons releasing groups) in the o-, moder p-position of the benzene ring exhibit; 1,1-diphenylmethanol, 1-phenylethanol, 1,1-diphenylethanol and other benzyl alcohols, each with a substituent in the neighboring position to the hydroxyl group. According to the invention are benzyl alcohols each have a substituent, e.g. an electron attracting Have group on their benzene ring, for example in the p-position, preferred, among which p-nitrobenzyl alcohol is particularly preferred.

The amount of diketting is, for example about 0.8 to about 10 mol, preferably about 0.9 to about 5 mol and more preferably about 1 to about 3 moles per mole of benzyl alcohol.

An important feature of the present Invention is that a reaction in the presence at least of a solvent carried out is by catalysis using a nitrogen-containing cyclic organic base. The nitrogen containing cyclic organic Base can be any cyclic organic base that at least has a nitrogen atom as the structural atom of their ring. To this Nitrogen-containing cyclic organic bases include, for example N-methylpyrrolidine, N-methylpiperidine, N-methylmorpholine, 1,5-diazabicyclo [5.4.0] undecene-5 (DBU), 1,5-diazabicyclo [4.3.0] nonen-5 (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO) and other cyclic amines, of which the cyclic tertiary amines are preferred are; Pyridine, 2-methylpyridine, 3-methylpyridine, N, N-dimethyl-4-aminopyridine and other pyridine compounds. Among them are the cyclic ones Amines preferred, among which N-methylpyrrolidine is particularly preferred is.

The amount of nitrogen containing cyclic organic base for example about 0.0001 to about 0.5 mol, and preferably about 0.001 to about 0.1 mole per mole of benzyl alcohol.

By using the nitrogen containing Cyclic organic base as a catalyst can be side reactions effective repressed to reduce by-products, and it can be high purity acetoacetic acid esters with less contamination from contaminants become.

The solvent suitable for use in the present invention is not specifically limited as long as it does not adversely affect the reaction. Preferred examples are benzene, benzene derivatives with at least one substituent on their benzene ring and other aromatic ones Solvent. These substituents include, for example, alkyl groups, for example C ₁ -C ₆ alkyl groups; Cycloalkyl groups, for example C ₃ -C ₈ cycloalkyl groups; and halogen atoms. If the benzene ring has a variety of substituents, these can be combined to form a ring with a carbon-carbon bond that builds the benzene ring. Examples of the benzene derivatives include toluene, ethylbenzene, cumene, butylbenzene, pentylbenzene, dodecylbenzene, cyclohexylbenzene, chlorobenzene and other mono-substituted derivatives; Xylenes, ethyltoluenes, propyltoluenes, cymenes, butyltoluenes, ethylisopropylbenzenes, diethylbenzenes, dipropylbenzenes, dipentylbenzenes, tetralin, dichlorobenzenes and other disubstituted derivatives; Hemimellites, pseudocumene, mesitylene and other trimethylbenzenes, triethylbenzenes, diethyltoluenes, dimethylethylbenzenes, dimethypropylbenzenes, triisopropylbenzenes and other tri-substituted derivatives; Prehniten, Isodurol, other tetraethylbenzenes and other tetra-substituted derivatives. Among them, toluene, ethylbenzene, o-xylene, m-xylene, p-xylene, mesitylene and other alkyl-substituted benzenes are preferred, with toluene being particularly preferred. Each of these solvents can be used alone or in combination.

The reaction temperature is, for example about –10 up to about 100 ° C, preferably about 0 to about 80 C and particularly preferably about 3 to about 60 C. The reaction can also be at about Run off smoothly at room temperature. The reaction can take place at normal pressure (Atmospheric pressure), under elevated Pressure (under a load) or under a reduced pressure carried out become. The reaction can also proceed smoothly at normal pressure. The response time is for example about 0.5 to about 30 hours, preferably about 1 to about 25 h and particularly preferably about 2 to about 20 h. The reaction temperature, the reaction pressure and the reaction time are appropriately selected dependent on the type of benzyl alcohol, the type of catalyst and others Conditions.

The reaction can be applied a conventional process, for example a batch process, a semi-batch process or a continuous process, carried out become. According to the Reaction carried out are added dropwise to a mixture containing the benzyl alcohol, the catalyst, the solvent and contains other components. In this case, diketene is added dropwise, for example via a Period of about 0.1 to about 10 hours, preferably over a period of time from about 0.2 to about 8 hours and particularly preferably over one Period from about 0.2 to about 6 hours.

The reaction becomes diketene with esterified the benzyl alcohol, giving the corresponding benzoacetoacetate receives.

After the reaction has ended, the Reaction products are separated and purified using a Separation device, e.g. by filtration, by concentration, by distillation, by extraction, by crystallization, by Recrystallization, by adsorption, by column chromatography and by combinations of these separation methods.

The acetoacetic acid esters include p-nitrobenzyl acetoacetate and other compounds that are strongly positive in the Ames test and therefore often as products to solutions, solved in solvents, processed to prevent their impact on operators and to make them easier to handle. These solvents for use in the present invention can conventional organic solvents his. In general, the solvent used in the reaction also used to manufacture the products. For example a solution of the acetoacetic acid ester in a concentration of about 25 to about 35% by weight in an aromatic solvent delivered as a product.

The component concentration (the Content) of the resulting product can be by high performance liquid chromatography (HPLC) analysis can be determined.

Examples

The present invention is under Reference to several examples and comparative examples below explained in more detail the However, the invention is by no means limited to these examples. All Unless otherwise stated, parts and percentages refer to each other is on weight. The results are shown in Table 1.

Example 1 In a collapsible piston the one with a stir, a dropping funnel, a cooler and equipped with a thermometer, 58 g of p-nitrobenzyl alcohol, 295 g of toluene and 0.32 g of N-methylpyrrolidine were introduced. To the one stirred at 30 ° C Mixture was over 33 g of diketene added dropwise over a period of 3 h to carry out the reaction. After completion After the addition, the mixture was allowed to stand at room temperature for 20 hours calmly. The reaction mixture was successively with 0.2 wt .-% Hydrochloric acid and ion-exchanged water, the organic layer dried and thereby a solution of p-nitrobenzylacetoacetate was obtained in ToIuol as a product. HPLC analysis showed that the product, apart from the toluene solvent, contained 99.07% by weight (87 g, yield: 97%) of p-nitrobenzylacetoacetate (NBAA) and 0.06 wt% (52 mg) impurities after the peak were eluted by NBAA. The result of the HPLC analysis is in the Table 1 given.

Example 2 A solution of p-nitrobenzyl acetoacetate in ToIuol was obtained as a product of the procedure of the example 1, but with the exception that 3-methylpyridine instead of N-methylpyrrolidine in an equimolar Amount were used as a catalyst. The result of the HPLC analysis of the product is given in Table 1.

Example 3 A solution of p-nitrobenzyl acetoacetate in ToIuol was obtained as a product of the procedure of the example 1, but this time pyridine instead of N-methylpyrrolidine in an equimolar amount was used as a catalyst. The result of the HPLC analysis of the Product is shown in Table -1.

Comparative Example 1

A solution of p-nitrobenzyl acetoacetate in ToIuol was obtained as a product according to the procedure of Example 1, however with the exception that this time triethylamine instead of N-methylpyrrolidine in an equimolar amount as a catalyst was used. HPLC analysis of the product showed that the product, apart from the toluene solvent, contained 97.94% by weight (79 g, yield: 88%) of p-nitrobenzylacetoacetate (NBAA) and 1.01 wt% (814 mg) impurities after the peak were eluted by NBAA. The contamination level was on the same basis as in Example 1 (NBAA content in product 87 g) converted to 897 mg by calculation according to the following formula: Impurity content (g) = 87 / 0.9794 × 0.0101. As a result found that the impurity content in Comparative Example 1 17 times that of Example 1 was (897 mg / 52 mg).

The result of the HPLC analysis is given in Table 1.

Analytical conditions

Column: Zorbax Rx-C8, 4.6 mm diameter × 250 mm Length, 5 μm column temperature: 40 ° C

solvent

• (A) aqueous Ammonium acetate solution (pH 4.7) and acetonitrile for the use of HPLC
• (B) acetonitrile for the use of HPLC

Strömungsrate: 1,0 ml/min
Detektor: UV-Wellenlänge 267 nmu
minimale Fläche 1000
Probenmenge: 30 bis 50 mg TABELLE 1

TABELLE 1 – Fortsetzung

In der Tabelle 1 sind die Messwerte in der Einheit [Fläche/Proben-Menge] angegeben. Der Ausdruck "Spuren" bedeutet, dass die Menge einer Probe nicht bestimmt werden konnte, obgleich eine Spur davon nachgewiesen wurde.Solvent mixtures with the following mixing ratios were used. The term "time" as used herein indicates the time elapsed from the injection of a sample.

Flow rate: 1.0 ml / min
Detector: UV wavelength 267 nmu
minimum area 1000
Sample amount: 30 to 50 mg TABLE 1

TABLE 1 - continued

Table 1 shows the measured values in the unit [area / sample quantity]. The term "trace" means that the amount of a sample could not be determined, although a trace of it was detected.

The expression "ND" means that the amount of a sample was below the detection limits.

The desired p-nitrobenzyl acetoacetate was eluted at an RT (retention time) of 10.5 min and the solvent ToIuol was eluted at RT of 13.7 min.

The invention has been made above with reference to such embodiments described which are currently regarded as preferred embodiments, however, it is clear that the invention applies to the described embodiments not limited is. Rather, the present invention includes various modifications and equivalents Orders within the spirit and scope of the following claims lie. The scope of the following claims is intended to the broadest interpretation to match all of these modifications and equivalents Structures and functions.

Claims (4)

Process for the preparation of an acetoacetic acid ester, which includes the step: allowing diketene to react with a benzyl alcohol in the presence of a solvent by catalysis using at least one nitrogen-containing cyclic organic base, making the corresponding acetoacetic acid ester is obtained. The method of claim 1, further comprising using a cyclic amine containing nitrogenous cyclic organic Base. The method of claim 1, further comprising using of p-nitrobenzyl alcohol as benzyl alcohol. The method of claim 1, further comprising using an aromatic solvent as a solvent.