US20070142661A1

US20070142661A1 - Process for preparing beta-keto nitriles and salts thereof

Info

Publication number: US20070142661A1
Application number: US11/605,604
Authority: US
Inventors: Klas Sorger; Jurgen Stohrer
Original assignee: Wacker Chemie AG
Current assignee: Wacker Chemie AG
Priority date: 2005-11-17
Filing date: 2006-11-29
Publication date: 2007-06-21
Also published as: EP1788001B1; TWI343390B; DE502006007576D1; ATE476451T1; EP1788001A1; CN100579992C; US8039563B2; JP2007138175A; TW200720293A; ES2347679T3; JP4617287B2; CN1966533A; US20070112117A1; DE102005054904A1

Abstract

A process for preparing β-keto nitrites or salts thereof is provided by reacting a nitrile with a carboxylic ester in the presence of an alkali metal alkoxide or alkaline earth metal alkoxide. Alcohol formed as a by-product is distilled off. The volume of alcohol distilled off is continually replaced by metering in an essentially equal volume of nitrile. The nitrile is provided in excess based on the carboxylic ester to be converted.

Description

BACKGROUND OF THE INVENTION

1. Field of the Invention
The invention relates to a process for preparing β-keto nitrites and salts thereof.
2. Background Art
β-Keto nitrites and salts thereof are important synthesis units for the preparation of active pharmaceutical ingredients and crop protection compositions.
E. H. Kroeker et al., J. Am. Chem. Soc., 1934, 56, p. 1171 discloses the preparation of 3-keto-4-methylvaleronitrile by reacting ethyl isobutyrate with acetonitrile in stoichiometric ratio in the presence of sodium ethoxide. In this reaction, sodium ethoxide is initially charged into a reactor with three one third portions of a 1:1 mixture of carboxylic ester and acetonitrile added. Excess nitrile is not used in this process. In each case, after addition of the ester-acetonitrile mixture, the alcohol formed as a by-product is distilled off. The yield of this preparation is only 44% of theory.
J. B. Dorsch et al., J. Am. Chem. Soc., 1932, 54, p. 2960 also discloses a process for preparing α-benzoalkyl cyanides, in which ester and alkoxide are initially charged in equimolar amounts into a reactor. A 25% excess of nitrile is then metered in. After the nitrile has been fully metered in, the alcohol formed is distilled off. In this process, only a 60% yield of the theoretical yield is obtained.
EP 220220 B1 describes the reaction of carboxylic esters with an excess of acetonitrile in the presence of the base sodium methoxide. The equilibrium is sifted to the product side by the use of excess acetonitrile and by the distillative removal of the alcohol formed in the reaction together with acetonitrile. In this process, a yield of β-keto nitrile sodium salt of 83% of theory can be achieved. However, this process has the disadvantage that a very large excess of from 13 to 14 equivalents of acetonitrile based on the carboxylic ester is employed. The majority of acetonitrile of greater than 12 equivalents is lost in the distillative removal of the alcohol. In addition, the high acetonitrile excess leads to a high total volume of the reaction mixture and hence to low concentrations and poor space-time yields. These disadvantages make the process uneconomical for industrial scale applications.
EP 1316546 A1 discloses a process in which acetonitrile is reacted with an excess of carboxylic ester in the presence of the base sodium methoxide. The equilibrium of the reaction is shifted to the product side by an excess of carboxylic ester and distillative removal of methanol formed together with acetonitrile The present process provides yields up to 82 to 86% of theory based on the conversion of acetonitrile. However, the process has the disadvantage that a majority of the carboxylic ester used in excess is lost in the workup, which makes the process uneconomical, especially for the conversion of valuable and hence expensive carboxylic ester substrates. In addition, the entire amount of carboxylic ester is initially charged in the process. This leads to a high total volume and hence to low concentrations and moderate space-time yields. For this reason too, the process is not economical for the industrial scale.
In the processes disclosed by EP 220220 B1 and EP 1316546 A1, excess acetonitrile and excess carboxylic ester serve simultaneously as a solvent that keeps the reaction mixture or the suspension which forms in a readily stirrable form and prevents the viscosity of the reaction mixture from increasing slurrying).
DE 10143858 A1 discloses the reaction of acetonitrile with diethyl oxalate and sodium methoxide in the presence of the tert-butyl methyl ether solvent under specific reaction conditions. In the process, acetonitrile is used only in a very small excess of not more than 15% based on the oxalic diester. The methanol which is formed is not distilled off to shift the equilibrium. This process only achieves a yield of not more than 67% of theory. The process is optimized especially for using oxalic diesters as the substrate. Because of the low achievable yields and the low space-time yields from the use of solvents, the process is not suitable for the broad industrial preparation of keto nitrites.
The processes known from the prior art do not provide satisfactory industrial scale preparation of β-keto nitriles or salts thereof. In particular, high chemical yields and high concentrations of the reactants (and hence high space-time performances) are desirable with large excesses of one reactant preferably avoided.

SUMMARY OF THE INVENTION

It is thus an object of the invention to provide an alternative process for preparing β-keto nitrites or salts thereof. It is a particular object of the invention to provide a process which is suitable for industrial use enabling high chemical yields of β-keto nitriles or salts thereof while working with high space-time yields and avoiding large excesses of acetonitrile or carboxylic ester.
An object of the invention is achieved by a novel process in which by-products formed are removed from the reaction system and the volume removed from the reaction system is replaced by metering in additional nitrile.
It has been surprisingly found that the preparation of β-keto nitriles or salts thereof succeeds in a particularly advantageous and economically viable manner in high space-time yields when alcohol formed during the reaction is distilled off and additional acetonitrile added while the alcohol is distilled off. The additional nitrile is metered in leading to the utilization of an excess of nitrile based on the ester converted in the overall assessment.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT(S)

The invention provides a process for preparing β-keto nitrites of the general formula (1a) or salts thereof of the general formula (1b)

wherein R¹is a linear or branched, saturated or unsaturated, nonaromatic, aromatic or heteroaromatic C₁-C₃₀-hydrocarbon radical which is cyclic or contains cyclic groups and is optionally substituted by Q;
R²is hydrogen or a linear or branched alkyl radical; Q is selected from the group comprising halogen, amino, hydroxyl, cyano, nitro, alkoxy, aryloxy, alkylthio, acyl, silyl, silyloxy, aryl, heteroaryl;
M is an alkali metal or alkaline earth metal ion,
The β-keto nitrites of the general formula (1a) or salts thereof of the general formula (1b) are formed by reacting a nitrile of the general formula (2)
R²—CH₂—C≡N (2)
wherein R²is as defined above with carboxylic esters of the general formula (3)

wherein R¹is as defined above and R is a C₁-C₁₀-alkyl radical, in the presence of an alkali metal alkoxide or alkaline earth metal alkoxide.
In this process, the alcohol R—OH formed as a by-product is distilled off (optionally in the form of an azeotrope) while continually replacing the distilled off volume with an essentially equal volume by metering in further nitrile. The nitrile is used in excess overall based on the carboxylic ester to be converted.
A feature of the invention is that the amounts of alcohol or azeotrope distilled off are compensated for in terms of volume by further metered addition of an excess of nitrile, so that the total volume of the reaction mixture remains essentially constant over the course of the reaction. An effect of the inventive procedure is that the steady-state concentration of the nitrile during the entire reaction is kept virtually constant, since the volume distilled off (which comprises essentially alcohol or an azeotrope of alcohol and nitrile) is continuously replaced by addition of additional nitrile. In this way, the reaction mixture does not continuously become depleted in nitrile. However, it is not necessary to work with large, especially steady-state, excesses of nitrile which lead to undesired dilution and reduce the space-time yield.
The increase in the amount of nitrile alone, i.e. working with a constant, in some cases also very high, excess of nitrile, has been found to be negative and does not lead to a significant shift in equilibrium to the product side.
An advantage of the process of the invention is that the excess of nitrile used is significantly less than in the known prior art processes, while the chemical yield is significantly higher.
In variations of the present embodiment, the C₁-C₃₀-hydrocarbon radicals R¹are linear or branched, saturated or unsaturated alkyl, aryl, heteroaryl, alkenyl or alkynyl radicals which are cyclic or contain cyclic groups. In heteroaromatic C₁-C₃₀-hydrocarbon radicals for R¹, the heteroatoms can preferably be selected from the group comprising oxygen, sulfur, nitrogen and phosphorus. The C₁-C₃₀-hydrocarbon radicals for R¹may optionally be substituted by Q, wherein Q is preferably be selected from the group comprising F, Cl, Br, I, CN, NO₂, OH, carbonyl, C₁-C₁₀-alkoxy, aralkyloxy, C₁-C₆-trialkylsilyl, C₁-C₆-trialkylsilyloxy, NH₂, C₁-C₁₀-alkylamino, di-C₁-C₁₀-alkylamino, C₁-C₆-trialkylsilylamino, C₁-C₆-trialkylsilyl-C₁-C₁₀-alkylamino, tert-butyloxycarbonylamino, benzyloxycarbonylamino, aryl, aralkyl, alkaryl, aralkenyl, alkenylaryl or heteroaryl radicals. The latter groups may in turn be substituted by radicals selected from the group of F, Cl, Br, I, CN, NH₂, NO₂, C₁-C₁₀-alkoxy radicals, C₁-C₁₀-alkylamino radicals or C₁-C₁₀-alkyl radicals.
Preferred unsaturated, aromatic and heteroaromatic radicals for R¹are selected from the group comprising allyl, vinyl, furyl, pyrrolyl, piperidinyl, pyrrolidinyl, quinolinyl, pyridyl, piperazinyl, imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolyl, isothiazolyl, indolyl, triazinyl, thienyl, thiophenyl, phenyl, and naphthyl. These groups may in turn be substituted by radicals selected from the group comprising methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, phenoxy, benzyloxy, amino, N-methylamino, N,N-dimethylamino, N-benzyl, N,N-dibenzyl, N-phthalimido, cyano, nitro, hydroxyl, fluorine, chlorine, and bromine.
Preferred saturated radicals for R¹are linear or branched alkyl radicals which are cyclic or contain cyclic groups and are optionally substituted by Q. More preferably, R¹is an alkyl radical selected from the group comprising methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
Preferred carboxylic esters of the general formula (3) include aliphatic, aromatic or heteroaromatic carboxylic esters in which the R¹radicals are optionally substituted by Q, alpha-, beta- or gamma-amino acid esters and alpha-, beta- or gamma-hydroxy acid esters. Preferably, these compounds are in enantiomerically enriched or enantiomerically pure form wherein the R¹radicals are each a saturated or unsaturated organic radical that is substituted by an amino or hydroxyl group and optionally by Q. The amino or hydroxyl groups in the alpha-, beta- or gamma-amino acid esters and alpha-, beta- or gamma-hydroxy acid esters may also be substituted or protected.
More preferably, Q is fluorine, chlorine, bromine, nitro, cyano, carbonyl, hydroxyl, amino, N-methylamino, N,N-dimethylamino, N-benzyl, N,N-dibenzyl, N-acetylamino, N-acetyl-N-methylamino, tert-butyloxycarbonylamino, N-benzyloxycarbonylamino, methoxy, ethoxy, tert-butyloxy, phenoxy, benzyloxy, acetyl, propionyl, pivalinoyl, phenyl, naphthyl, benzyl, furyl, piperidinyl, pyrrolidinyl, quinolinyl, pyridyl, piperazinyl, imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolyl, isothiazolyl, indolyl, triazinyl, thienyl or thiophenyl. These groups are optionally substituted by radicals selected from the group comprising methyl, ethyl, n-propyl, isopropyl, butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, allyl, vinyl, phenyl, furyl, piperidinyl, pyrrolidinyl, quinolinyl, pyridyl, piperazinyl, imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolyl, isothiazolyl, indolyl, triazinyl, thienyl, thiophenyl, fluorine, chlorine, bromine, nitro, cyano, amino, hydroxy, methoxy, ethoxy, phenoxy, trimethylsilyl, triethylsilyl, acetyl, propionyl, amino, N,N-dimethylamino, N-benzyl, N-acetylamino, N-acetyl-N-methylamino or N-benzyloxycarbonylamino, and also acetyl-, amino-, N-methylamino-, N,N-dimethylamino-, N-benzyl-, N-acetylamino-, N-acetyl-N-methylamino-, N-benzyloxycarbonylamino-, nitro-, methyl-, ethyl-, propyl-, isopropyl-, butyl-, sec-butyl-, tert-butyl-, methoxy-, ethoxy-, phenoxy-, acetoxy-, benzyloxy-, trimethylsilyl-, trimethylsilyloxy, triethylsilyloxy-, fluoro-, chloro-, bromo-, iodo- and cyanophenyl or -naphthyl.
Preferred radicals for R²are hydrogen and C₁-C₁₀-alkyl radicals, especially methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl; in this context especially methyl, ethyl, n-propyl and isopropyl.
More preferably, nitriles of the general formula (2) are selected from the group comprising acetonitrile, propionitrile and butyronitrile, especially acetonitrile.
In the esters of the general formula (2), the C₁-C₁₀-alkyl radicals R are preferably selected from the group comprising methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, especially methyl, ethyl, n-propyl and isopropyl.
Suitable alkoxides include alkali metal alkoxides and alkaline earth metal alkoxides. Preferably, the alkoxides are metal alkoxides, especially the methoxides, ethoxides, propoxides, butoxides and pentoxides of sodium and potassium. More preferably, the alkoxides are selected from sodium methoxide and sodium ethoxide. The alkoxide is used in solid form or as a solution in alcohol or other suitable solvents. Preferably, the alkoxide is in solid form, which has an advantageous effect on the space-time yields.
The alkoxides are used in a ratio of from 0.5 to 2:1, preferably from 0.7 to 1.5:1. More preferably, the alkoxides are used in a ratio from 0.9 to 1.1:1, based on the carboxylic ester. Most preferably, the ratio is such that the stoichiometric (equimolar) amounts of alkoxide and carboxylic ester are used.
The nitrile, especially acetonitrile, is used in excess overall based on the carboxylic ester. In one variation, the ratio of nitrile to carboxylic ester to be converted is from 2 to 10:1. Preferably, the ratio of nitrile to carboxylic ester to be converted is from 3 to 7:1. More preferably, the ratio of nitrile to carboxylic ester to be converted is from 4 to 6:1.
In another embodiment of a process of the invention, 0.3 to 2 equivalents of nitrile, (especially acetonitrile) based on carboxylic ester, are initially charged together with carboxylic ester and alkoxide into a reaction vessel. Preferably, 0.5 to 1.5 equivalents of nitrile, (especially acetonitrile) based on carboxylic ester, are initially charged together with carboxylic ester and alkoxide into a reaction vessel. More preferably, 0.9 to 1.1 equivalents of nitrile, (especially acetonitrile) based on carboxylic ester, are initially charged together with carboxylic ester and alkoxide into a reaction vessel. In this way, a very high concentration of the mixture is achieved. The sequence of mixing of nitrile, carboxylic ester and alkoxide may be as desired. Preferably alkoxide is added first followed by addition of nitrile and carboxylic ester. It is also possible to first add alkoxide and carboxylic ester and then nitrile, (optionally at elevated temperature). The reaction is effected at elevated temperature between 50 and 150° C. Preferably, the temperature is from 70 to 120° C.
Alcohol is formed as the reaction progresses. To shift the equilibrium, the alcohol formed in the course of the reaction, or the azeotropic mixture of alcohol and nitrile is distilled continually out of the reaction mixture. The azeotropic mixture in this scenario regularly forms depending on the selection of the nitrile especially when acetonitrile is used. In the case of a low-boiling carboxylic ester, the azeotropic mixture may include alcohol, nitrile and carboxylic ester, The alcohol formed is regularly distilled off as an azeotrope together with the acetonitrile with additional acetonitrile continually added during the reaction, either continuously or in portions. This methodology may also be used for other nitrites.
The volume of alcohol or azeotrope distilled off (e.g., especially of the alcohol-acetonitrile mixture) corresponds approximately to the volume of additional nitrile added. Accordingly, the reaction takes place at maximum concentration, which leads to very high space-time yields.
The nitrile (e.g., acetonitrile) is added generally in a ratio from 0.5 to 9:1 based on carboxylic ester. Preferably, this ratio is from 1 to 6:1. More preferably, this ratio is from 2 to 5:1.
In a variation of the process of the present invention, generally a 2- to 10-fold excess of nitrile is used. Preferably a 3- to 7-fold excess of nitrile is used. More preferably, a 4- to 6-fold excess of nitrile is used. These amounts are particularly useful when the nitrile is acetonitrile.
Contrary to the prior art processes, it has been surprisingly found that the addition of nitrile during the distillative removal of the alcohol formed or azeotrope thereof with the nitrile allows a high, especially steady-state, excess of acetonitrile (for example from 12 to 13 equivalents in the process known from EP 220022 B1) based on carboxylic ester to be avoided. The processes of the present invention allow high chemical yields of >85-90% of theory with virtually complete conversion based on the carboxylic ester. Surprisingly, for this purpose, a total of only, 3 to 6 equivalents of nitrile are added during the reaction. Preferably, a total of only 2 to 5 equivalents are added during the reaction. The continual metered addition of nitrile during the distillative removal of alcohol has a surprisingly advantageous influence on the reaction.
In a particularly preferred embodiment of the process of the present invention, the entire amount of carboxylic ester and alkoxide to be converted is initially charged with a portion of the total amount of nitrile (preferably in a stoichiometric (equimolar) ratio) used which has an advantageous effect on the reaction time, the space-time yield and the profile of the entire reaction. For example, when a suspension of one equivalent of sodium methoxide, one equivalent of methyl cyclopropanecarboxylate and one equivalent of acetonitrile is heated to 90° C. for 1 hour, a clear solution is surprisingly formed in spite of the high concentration of reactants and absence of additional solvent. Addition of further acetonitrile to this solution allows methanol or a mixture of methanol and acetonitrile to be distilled off in a technically simple manner without slurrying with the equilibrium of the reaction shifted to the product side (cf. Example 1a). It is surprising that at temperatures of more than 70° C., a clear homogeneous, highly mobile solution forms after a short reaction time, without any need to add solvents such as polar aprotic solvents (e.g., excess acetonitrile), or ethers such as tetrahydrofuran or methyl tert-butyl ether.
A high excess of acetonitrile or carboxylic ester, which serves as a solvent to prevent slurrying in the known processes, is thus not required. When, in contrast, as described in E. H. Kroeker et al., J. Am. Chem. Soc., 1934, 56, p. 1171, excess alkoxide based on stoichiometric amounts of carboxylic ester and acetonitrile is initially charged, a slurrylike suspension which is difficult to stir is formed in the course of heating, and tends to form crusts on the vessel walls and conglutinate. This has a disadvantageous effect on reaction times, yields and purities of the products prepared leading to problems, especially in industrial scale implementation.
In contrast, in the process according to the invention, a stoichiometric mixture of alkoxide, nitrile and ester without solvent is heated and further nitrile added continually during the distillative removal of alcohol-nitrile mixture such that virtually full conversion based on ester proceeds within surprisingly very short reaction times. For example, consider a mixture of one equivalent of sodium methoxide, one equivalent of methyl cyclopropanecarboxylate, and a total of 4.5 equivalents of acetonitrile (of which initially only one equivalent has been initially charged together with the other reactants) heated to 90° C. The methanol-acetonitrile azeotrope which forms is distilled off and an amount of acetonitrile essentially identical to the volume is added continuously with the methyl cyclopropanecarboxylate being fully converted after only 3.5 hours. In contrast thereto, in the process known from E. H. Kroeker et al., J. Am. Chem. Soc., 1934, 56, p. 1171, stoichiometric amounts of acetonitrile, sodium ethoxide and ethyl isobutyrate are used with only 44% of the keto nitrile being obtained after 9 hours at from 115 to 120° C.
It is additionally surprising that, when the reaction in the process according to the invention is performed, only very small losses as a result of cocondensation of carboxylic ester or nitrile, especially acetonitrile, occur. When, in contrast, the addition of the nitrile to the mixture of ester and alkoxide is dispensed with, especially for esters of aliphatic carboxylic acids, the undesired formation of condensation products of the ester caused by base-catalyzed cocondensation is observed in the course of heating of the mixture of ester and alkoxide. Such condensation products can surprisingly be avoided almost entirely by the process according to the invention.
As a result of the small steady-state excess of acetonitrile in the reaction mixture, which is inherent to the process according to the invention, undesired cocondensation products of the acetonitrile are also formed only in a minimal fraction. The metered addition of acetonitrile to a clear stoichiometric mixture of sodium methoxide, carboxylic ester and acetonitrile with simultaneous distillative removal of methanol-acetonitrile mixture has a particularly advantageous effect on the minimization of cocondensation products of the acetonitrile and polymerization of acetonitrile.
In contrast to EP 220220, considerably more fractions of undesired by-products are formed when a mixture of one part of methyl caproate and 13 parts of acetonitrile is heated to reflux, some of the methanolic sodium methoxide solution is metered in and a mixture of methanol and acetonitrile is distilled off at the same time. This result from the self-addition or -condensation of the acetonitrile present in high excess in the presence of the base.
In a particularly preferred embodiment of the process of the invention, a stoichiometric mixture of alkoxide, nitrile and carboxylic ester is initially charged to a reaction vessel without additional solvent. The mixture is heated with additional nitrile metered in continuously as alcohol or alcohol-nitrile mixture is distillatively removed. until virtually full conversion based on carboxylic ester has been attained. Subsequently, residues of alcohol and nitrile are distilled off as far as possible, optionally after addition of an inert solvent. The keto nitrile salt which forms initially is filtered off, or, alternatively, the mixture is worked up under aqueous conditions to release the keto nitrile. In this way, particularly high product yields and purities can be achieved within short reaction times of from 3 to 6 hours at maximum concentration and particularly high space-time yields, and hence in a very economically viable reaction overall.
The inventive reaction of the carboxylic ester with the nitrile in the presence of an alkoxide can also be carried out in the presence of an inert solvent. Suitable inert solvents are ethers (example e.g., tert-butyl methyl ether, dibutyl ether, dimethoxyethane or diethoxyethane), high-boiling glycols (example e.g., polyethylene glycols), alcohols (e.g., isopropanol, n-butanol, 2-butanol or tert-butanol), hydrocarbons (e.g., toluene, xylene or mesitylene), or polar aprotic solvents (e.g., N,N-dimethylformamide, dimethyl sulfoxide or N-methyl-pyrrolidone). Particularly useful solventions include dibutyl ether, dimethoxyethane, diethoxyethane, toluene, N,N-dimethylformamide and dimethyl sulfoxide. Preferably, the solvent is toluene.
In a particularly preferred embodiment of the process of the invention, the reaction is, however, performed without addition of additional inert solvents. This has an advantageous effect on the space-time yield.
Toward the end of the reaction, there may be precipitation of keto nitrile salt of the general formula (1b) formed. In order to complete the precipitation, it is possible to distill off residual nitrile, if appropriate together with residues of alcohol or unconverted ester. The keto nitrile salt can then be isolated by filtration. Optionally, the filtration can be performed in the presence of an inert solvent, especially when the mixture is filtered at temperatures below the reaction temperature, in particular between 10 and 80° C. Suitable inert solvents are the abovementioned solvents, especially toluene, dibutyl ether, tert-butyl methyl ether, dimethoxyethane or diethoxyethane.
The keto nitrile salts prepared by the process of the invention are surprisingly of very high purity and can be processed further directly in most cases. Optionally, the keto nitrile salts can also be purified further, for example by washing, recrystallization or extraction. The keto nitrites can be released in particularly pure form from the purified keto nitrile salts.
To directly release keto nitrile from the prepared keto nitrile salt, the mixture is hydrolyzed with water or aqueous acid upon completion of reaction. The hydrolysis may also be performed at significantly higher temperatures than room temperature without noticeable yield. The hydrolysis is effected at temperatures between 0 and 100° C. Preferably, the hydrolysis is effected at temperatures from 30 to 80° C. For hydrolysis, water or aqueous acid, for example hydrochloric acid or sulfuric acid, is introduced into the reaction mixture until solids dissolve fully. Alternatively, it is also possible to meter the reaction mixture into water or aqueous acid. When water is used for the hydrolysis, keto nitrile salt dissolves in the form of its enolate of the general formula (1b) in the aqueous alkaline phase. Optionally, the aqueous phase can be extracted with organic, water-immiscible solvent. The aqueous phase is then acidified with an acid to pH from 0 to 8, which releases keto nitrile of the general formula (1a). Preferably, the aqueous phase is then acidified with an acid to pH from 2 to 5. When aqueous acid is used directly for the hydrolysis, keto nitrile is immediately released. The released keto nitrile is finally extracted with organic, water-immiscible solvent and optionally purified, for example by filtration, distillation, crystallization or extraction. It is also possible to perform the workup and release of keto nitrile by adding a nonaqueous acid, for example formic acid or acetic acid, or to meter the reaction mixture into the nonaqueous acid. Released keto nitrile can then be isolated directly by distillation, filtration or optionally, after addition of water or of an aqueous acid, by extraction with organic water-immiscible solvent. The keto nitrile salt is preferably isolated by filtration, or keto nitrile is released by aqueous workup.
The pressure range of the reaction is not critical and can vary within wide limits. The pressure is typically from 0.01 to 20 bar; the reaction is preferably performed under standard pressure (atmospheric pressure).
The reaction is preferably performed with inertization with an inert protective gas, especially nitrogen or argon. The reaction can be performed continuously or batchwise.
All symbols above of the formulae above are each defined independently of one another.
In the examples which follow, unless stated otherwise in each case, all amounts and percentages are based on the weight, all pressures are 0.10 MPa (abs.) and all temperatures are 20° C. The examples serve to further illustrate the process according to the invention and are in no way to be interpreted as a restriction.

EXAMPLE 1A

Preparation of 3-cyclopropyl-3-ketopropionitrile sodium salt (Workup by Filtration)

At room temperature, a four-neck flask with internal thermometer, dropping funnel, precision glass stirrer and attached distillation apparatus with separating column under nitrogen protective gas is initially charged with 21.6 g of solid sodium methoxide (0.4 mol), and 16.4 g of acetonitrile (0.4 mol) and 40.0 g of methyl cyclopropanecarboxylate (0.04 mol) are metered in. The suspension is heated to 85° C. and stirred for 1 hour to form a clear mixture. Subsequently, a mixture of methanol and acetonitrile is distilled off at an initial top temperature of 63° C. As the distillative removal begins, further acetonitrile is metered into the reaction mixture (total of 74 g, 1.8 mol), the volume of added acetonitrile corresponding to the methanol-acetonitrile mixture distilled off. In the course of the distillative removal, the internal temperature of the reaction mixture is increased from 90 to 95° C. Toward the end of the distillative removal of MeOH/acetonitrile, a suspension forms. Finally, almost pure acetonitrile is distilled off at a top temperature of 80° C. (composition of the entire distillate in % by weight by GC: 72.4% acetonitrile, 26% methanol, 1.6% methyl cyclopropanecarboxylate). Monitoring of conversion (NMR, GC) shows that the ester is converted apart from 2 mol %. Subsequently, 40 ml of toluene are added to the reaction mixture and residual acetonitrile is distilled off (and can be recovered). The mixture is cooled to 70° C. and filtered through a glass frit. The filtercake is washed twice with 20 ml each time of acetone and dried under reduced pressure. 45.1 g of 3-cyclopropyl-3-ketopropionitrile sodium salt of pale yellowish color are obtained, which corresponds to a yield of 86% of theory (chem. purity: >95%).

EXAMPLE 1B

Preparation of 3-cyclopropyl-3-ketopropionitrile (Aqueous Workup)

Procedure is initially analogous to that in Example 1a. The toluenic suspension is cooled to 50° C. With cooling, 40 ml of water are metered in, which forms a clear solution. Subsequently, the pH is adjusted to 4 with 20% hydrochloric acid. After phase separation, the aqueous phase is extracted twice with 20 ml each time of methylene chloride. The combined organic phase is washed with 20 ml of 8% NaHCO₃solution. After distillative removal of solvent, 3-cyclopropyl-3-ketopropionitrile of slightly brownish color is obtained in a yield of 36.2 g (83% of theory, chem. purity: 98%).

EXAMPLE 2A

Preparation of 4,4-dimethyl-3-ketovaleronitrile sodium salt (Workup by Filtration)

In an analogous procedure to Example 1a using 10 g of methyl pivalate (0.086 mol), 4.65 g of NaOMe (0.086 mol) and 17.7 g of acetonitrile (0.43 mol), 3.5 g (0.086 mol) are initially charged into the reaction flask, after filtration, washing and drying, 12.7 g of the sodium salt of 4,4-dimethyl-3-ketovaleronitrile (93% of theory) are obtained in a purity of 97%.

EXAMPLE 2B

Preparation of 4,4-dimethyl-3-ketovaleronitrile (Aqueous Workup)

The procedure of this example is analogous to that in Example 1a using the amounts of Example 2a. This example results in 9.8 g of 4,4-dimethyl-3-ketovaleronitrile (91% of theory) in a purity of 98.2% (GC).

EXAMPLE 3

Preparation of 3-ketocapronitrile (Aqueous Workup)

In an analogous procedure to Example 1b, 10 g of methyl butyrate (0.098 mol), 5.28 g of NaOMe (0.098 mol) and 4.02 g of acetonitrile (0.098 mol) are initially charged into the reaction flask. The mixture is heated to 85° C. After 2 hours, the distillative removal of a mixture of MeOH and acetonitrile is commenced, and, as the distillative removal begins, an additional 16.1 g of acetonitrile (0.39 mol) are metered in continuously. After an additional 2.5 h of distillative removal of MeOH/acetonitrile and metering in of additional acetonitrile, 20 ml of toluene are added and residual MeOH/acetonitrile are distilled off. After cooling to 60° C., 10% hydrochloric acid is added down to a pH of 3. After phase separation, the aqueous phase is extracted twice with 20 ml each time of methylene chloride. The organic phase is washed once with 15 ml of 5% NaHCO₃solution. After the toluene and methylene chloride solvents is distilled off, 3-ketocapronitrile is obtained in the form of an almost colorless liquid in a yield of 8.5 g based on butyric ester converted (89% of theory, chem. purity: 98.6%). By GC, 12 mol % of methyl butyrate are lost together with MeOH and acetonitrile distilled off.

EXAMPLE 4

Preparation of 3-phenylpropionitrile (Aqueous Workup)

In analogous procedure to Example 1b, 10 g of methyl benzoate (0.074 mol), 4.0 g of NaOMe (0.074 mol) and 3.01 g of acetonitrile (0.074 mol) are initially charged. The mixture is heated to 90° C. After 1.5 hours, a clear solution forms, and the distillative removal of a mixture of MeOH and acetonitrile is commenced. As the distillative removal begins, an additional 12.4 g of acetonitrile (0.29 mol) are metered in continuously. After an additional 2.5 hours of distillative removal of MeOH/acetonitrile and metering in of additional acetonitrile, 20 ml of toluene are added, and residual MeOH/acetonitrile is distilled off. After cooling to 40° C., 10% hydrochloric acid is added down to a pH of 3, which dissolves solids that form. After phase separation, the aqueous phase is extracted twice with 20 ml each time of methylene chloride. The organic phase is washed once with 10 ml of 8% NaHCO₃solution. After the toluene and methylene chloride solvents is distilled off, 3-phenylpropionitrile is obtained in the form of an almost colorless solid in a yield of 10.1 g (92% of theory, chem. purity: 97%). After recrystallization from ethanol, colorless solid having an m.p. of 82° C. is obtained.

Claims

1. In a process for preparing β-keto nitrites of the general formula (1a) or salts thereof of the general formula (1b)

by reacting a nitrile of the general formula (2)

R²—CH₂—C≡N (2)

with carboxylic esters of the general formula (3)

in the presence of an alkali metal alkoxide or alkaline earth metal alkoxide,

wherein:

R¹is a linear or branched, saturated or unsaturated, nonaromatic, aromatic or heteroaromatic C₁-C₃₀-hydrocarbon radical which is cyclic or contains cyclic groups and is optionally substituted by Q;

R²is hydrogen or a linear or branched alkyl radical;

Q is selected from the group comprising halogen, amino, hydroxyl, cyano, nitro, alkoxy, aryloxy, alkylthio, acyl, silyl, silyloxy, aryl, heteroaryl; and

M is an alkali metal or alkaline earth metal ion,

R is a C₁-C₁₀-alkyl radical,

the improvement comprising:

a) distilling off the alcohol R—OH formed as a by-product, optionally in the form of an azeotrope;

b) continually replacing the volume distilled off with an essentially equal volume of additional nitrile by such that overall the nitrile is provided in excess based on the carboxylic ester to be converted.

2. The process of claim 1, wherein the carboxylic ester, the nitrile and the alkali metal or alkaline earth metal alkoxide are initially charged into a reaction vessel in essentially equimolar amounts.

3. The process of claim 1, wherein the ratio of total nitrile added to carboxylic ester is from 4 to 6:1.

4. The process of claim 1, wherein the continual further metered addition of the nitrile is effected continuously or in portions.

5. The process of claim 1, wherein the alkali metal alkoxide used is sodium methoxide or sodium ethoxide.

6. The process of claim 1, wherein the nitrile is selected from the group comprising acetonitrile, propionitrile and butyronitrile.

7. The process of claim 1, wherein the carboxylic esters are selected from the group comprising optionally Q-substituted and optionally enantiomerically enriched or enantiomerically pure alpha-, beta- or gamma-amino acid esters or alpha-, beta- or gamma-hydroxy acid esters.

8. The process of claim 1, wherein the reaction is effected at a temperature from 70 to 120° C.

9. The process of claim 1, wherein the reaction is performed in the presence of an inert solvent.

10. The process of claim 1, wherein the reaction is performed without addition of additional inert solvents.

11. The process of claim 1, wherein the ratio of total nitrile added to carboxylic ester is from 2 to 10:1.

12. The process of claim 1, wherein the ratio of total nitrile added to carboxylic ester is from 3 to 7:1.

13. In a process for preparing β-keto nitrites of the general formula (1a) or salts thereof of the general formula (1b)

by reacting a nitrile of the general formula (2)

R²—CH₂—C≡N (2)

with carboxylic esters of the general formula (3)

in the presence of an alkali metal alkoxide or alkaline earth metal alkoxide,

wherein:

R²is hydrogen or a linear or branched alkyl radical;

M is an alkali metal or alkaline earth metal ion,

R is a C₁-C₁₀-alkyl radical,

the improvement comprising:

b) continually replacing the volume distilled off with an essentially equal volume of additional nitrile by such that overall the nitrile is provided in excess based on the carboxylic ester to be converted, wherein the ratio of total nitrile added to carboxylic ester is from 4 to 6:1.

14. The process of claim 13, wherein the continual further metered addition of the nitrile is effected continuously or in portions.

15. The process of claim 13, wherein the alkali metal alkoxide used is sodium methoxide or sodium ethoxide.

16. The process of claim 13, wherein the nitrile is selected from the group comprising acetonitrile, propionitrile and butyronitrile.

17. The process of claim 13, wherein the carboxylic esters are selected from the group comprising optionally Q-substituted and optionally enantiomerically enriched or enantiomerically pure alpha-, beta- or gamma-amino acid esters or alpha-, beta- or gamma-hydroxy acid esters.

18. The process of claim 13, wherein the reaction is performed in the presence of an inert solvent.

19. In a process for preparing β-keto nitriles of the general formula (1a) or salts thereof of the general formula (1b)

by reacting a nitrile of the general formula (2)

R²—CH₂—C≡N (2)

with carboxylic esters of the general formula (3)

in the presence of an alkali metal alkoxide or alkaline earth metal alkoxide,

wherein:

R²is methyl;

M is an alkali metal or alkaline earth metal ion,

R is a C₁-C₁₀-alkyl radical,

the improvement comprising:

20. The process of claim 13, wherein the carboxylic esters are selected from the group comprising optionally Q-substituted and optionally enantiomerically enriched or enantiomerically pure alpha-, beta- or gamma-amino acid esters or alpha-, beta- or gamma-hydroxy acid esters.