WO2013121018A1 - Synthesis of cyanocarboxylic acid alkyl esters - Google Patents

Abstract

Provided is a process for obtaining a compound of formula (I): N≡C-CH₂-A-C(O)-OR, wherein Hal is halogen selected from F, Cl, Br or I, A denotes a bond or a divalent spacer selected from alkylene and arylene groups, and R is a C_1-4 alkyl group, by reacting a compound of formula (II): Hal-CH₂-A-C(O)-OR, wherein Hal is a halogen atom selected from F, Cl, Br and I, and wherein A and R are as defined above, with hydrogen cyanide in the presence of a first base, wherein the molar ratio between hydrogen cyanide and said first base is from 1:0.3 to 1:0.95 and the molar ratio between hydrogen cyanide to the compound of formula (II) is at least 1:1.

Description

SYNTHESIS OF CYANOCARBOXYLIC ACID ALKYL ESTERS FROM HALOCARBOXYLIC ACID ESTERS

The present invention relates to a process for producing cyanocarboxylic acid alkyl esters of formula

N≡C-CH₂-A-C(O)-OR (I),

wherein A denotes a bond or a divalent spacer selected from alkylene and arylene groups, and R is a Ci_-4 alkyl group.

Background Art

Halocarboxylic acid alkyl esters and cyanocarboxylic acid alkyl esters are both important building blocks in the agrochemical and pharmaceutical industry. Typically, cyanocarboxylic acid alkyl esters such as cyanoacetates are obtained from

corresponding halocarboxylic acid metal salts, for example sodium chloroacetate, which react with a cyanide to give the corresponding cyanocarboxylic acid salts such as sodium cyanoacetate. The acid is set free by mixing, for example, with sulphuric acid and is esterified with the desired alcohol. Alternatively, esterification of a halocarboxylic acid is the first step which is optionally followed by a cyanidation step. A broad variety of esterification reactions of carboxylic acids with lower alcohols is known in the art. A reactive distillation for the preparation of methyl acetate using Katapak®-S for structured column packing, wherein the ester is withdrawn as an overhead product, is known from Chemie Technik, 29, 2000, 42-45.

DE-A-19539962 discloses a continuous process for the esterification of chloroacetic acid with a lower alcohol in the presence of an acidic catalyst, wherein the product is withdrawn from the vapour phase of the reaction as an ester-water mixture which separates into two phases. The starting acid and the acidic catalyst are contained in the bottom of the reaction vessel.

DD-A-97416 discloses a process for the continuous preparation of methyl monochloroacetate by reacting monochloroacetic acid and methanol in the liquid phase in a reactor vessel, wherein the vapour is distilled and the product is withdrawn at about the middle of the distillation column, while the column head stream is withdrawn and divided into two parts, one of which is reintroduced into the system at the column head while the other one is introduced directly into the reactor vessel. DD-A-97416 also refers to several prior art processes wherein methyl monochloroacetate is obtained by reacting monochloroacetic acid with methanol in the presence of concentrated mineral acids, by reaction with dimethylsulfate or by transesterification of higher esters. EP-A-0 315 096 discloses the preparation of monochloroacetic acid Ci_-4 alkyl esters by reacting a melt of monochloroacetic acid comprising a catalyst with a Ci_-4 alcohol and removing product and reaction water as an azeotrope by distillation.

EP-A-0 424 861 discloses the reaction of a C2-5 carboxylic acid, preferably an aliphatic C2-5 carboxylic acid, and a Ci_-4 alcohol in the presence of a catalyst in a reactive distillation column, wherein an azeotrope of reaction consisting of water and ester is withdrawn as an overhead product.

EP-A-0 999 206 discloses the preparation of 2-ethyl-hexyl monochloroacetate by reacting monochloroacetic acid with 2-ethyl-hexan-1 -ol in the presence of sulphuric acid, water and toluene. The product is downstream processed by washing with aqueous NaHCO3 solution and vacuum distillation. EP-A-0 999 206 further discloses the preparation of alkyl cyanoacetates by reacting the corresponding alkyl monochloroacetates with HCN in the presence of a tertiary alkylamine. Although EP-A-0 999 206 claims that cyanidation can be carried out without solvent, all examples have been carried out in the presence of acetonitrile as a solvent.

EP-A-0 999 206 also refers to DE-A-1 951 032 and EP-A-0 032 078 which also discloses cyanidation in the presence of acetonitrile as a solvent.

US-A-2985682 discloses the reaction of alkyl monohaloacetates with HCN in the presence of NH₃ which renders the process dangerous to be carried out on large scale. After 7 h a yield of only 50% is disclosed.

RO-B-1 13554 discloses the reaction of monochloroacetic acid with a Ci_-4 alcohol in the presence of an acidic catalyst in a gas-liquid media at a temperature from 50 to 150 °C to obtain the respective ester, wherein the product is withdrawn from the vapour phase and cooled, followed by vacuum rectification of the raw ester. Although not explicitly disclosed, the ester is condensed and thus withdrawn from the vapour phase of the reaction. RO-A-94544 discloses the preparation of alkyl monochloroacetates reacting a lower aliphatic alcohol with monochloroacetic acid in a reaction column, wherein the product is withdrawn from the column head which is heated to a temperature of from 15 to 20 °C above the boiling point of the respective ester-water azeotrope. RO-A-83054 discloses the liquid-liquid extraction of Ci- esters of monochloroacetic acid, wherein water is added to the reaction mixture comprising sulphuric acid, monochloroacetic acid and the respective alcohol to recover the ester from the aqueous layer.

WO-A-90/14328 discloses the reaction of glacial acetic acid and methanol in the presence of an acidic catalyst to obtain methyl acetate at the column head in a reactive distillation column having an extractive distillation section and a methyl acetate/acetic acid rectification section, wherein the acidic catalyst, water and methanol are withdrawn from the column bottom. The prior art processes for the esterification of halocarboxylic acids suffer from the drawback that separation of halocarboxylic acid alkyl esters from alcohols may cause problems during downstream processing due to emulsification. Moreover, removal of water from carboxylic acid alkyl esters is laborious because of azeotrope formation. Known processes wherein esters are withdrawn from the vapour phase, either as an overhead product or at an intermediate distillation tray, are characterized by high energy consumption and in each case the product contains a certain amount of water. In the classical approach of ester preparation, where reaction and purification occur in different unit operations, the mineral acid used as a catalyst, due to the higher boiling point of the ester compared to the corresponding alcohol, remains in the ester-phase and has to be separated in an additional step. While the use of HCI as a mineral acid is an interesting option as it is also a side-product in the production of chloroacetic acid, use thereof leads to a complex downstream process due to the formation of many azeotropic mixtures. Processes reacting for example ethyl 2-chloroacetate with HCN and a base for the preparation of cyanocarboxylic acid alkyl esters such as ethyl 2-cyanoacetate suffer from the drawback of undesired side products due to the formation of polymeric HCN and cyanidation products such as 2-cyanosuccinic acid diethyl ester (DECS) and 2-cyano-2-ethoxycarbonylmethyl-succinic acid diethyl ester (TECP). Similar side products can be expected in the esterification of other halo carboxylic acid alkyl esters of formula II, wherein A and R as defined above. Formation of polymeric HCN firstly results in loss of HCN and secondly may also clog lines and equipment such as circulating pumps. Another side effect of polymeric HCN is discoloration of the products. Only about 50 ppm of polymeric HCN is sufficient to colorize the product dark brown to black. Furthermore, the formation of side products also reduces yields and complicates purification of the desired product.

Therefore, an object of the invention is to provide a process for the preparation of a cyanocarboxylic acid alkyl ester from a halocarboxylic acid alkyl ester, as well as a combined process, starting with preparation of a halocarboxylic acid alkyl ester from a halocarboxylic acid and subsequent reaction to obtain the intermediate for the preparation of cyanocarboxylic acid alkyl ester.

Provided is a process for the preparation of a compound (cyanocarboxylic acid alkyl ester) of formula

N≡C-CH₂-A-C(O)-OR I,

wherein A denotes a bond or a divalent spacer selected from alkylene and arylene groups, and R is a Ci_-4 alkyl group, said process comprising

reacting a compound (halocarboxylic acid alkyl ester) of formula

Hal-CH₂-A-C(O)-OR II,

wherein Hal is a halogen atom selected from F, CI, Br and I, and wherein A is as defined above, with hydrogen cyanide (HCN) in the presence of a first base, wherein the molar ratio between hydrogen cyanide and said first base is from 1 :0.3 to 1 :0.95 and the molar ratio between hydrogen cyanide to the compound of formula II is in the range from 1 :1 to 1 :4. Expediently, the obtained cyanocarboxylic acid alkyl ester of formula I is separated from the reaction mixture. Separation of the product can be carried out for example by addition of water and phase separation. The aqueous phase mainly comprises the halide salt of the first base. Preferably the first base is an organic base, more preferably an amine base. After phase separation the organic phase mainly comprises said compound of formula I.

In the process for producing a cyanocarboxylic acid alkyl ester of formula I, the halogen atom of an halocarboxylic acid alkyl ester of formula II used as the starting material is substituted by the CN group of the hydrogen cyanide. Preferably, Hal is fluorine, chlorine, bromine or iodine, more preferably is chlorine or bromine, most preferably is chlorine.

The process for producing a cyanocarboxylic acid alkyl ester of formula I, wherein A and R are as defined above, starts from a corresponding halocarboxylic acid alkyl ester of formula II which is commercially available. The present invention also provides an advantageous process for the preparation of the compound of formula II by a reactive distillation process described below. Thus, according to the invention the process for producing a halocarboxylic acid alkyl ester of formula II and the process for producing a cyanocarboxylic acid alkyl ester of formula I advantageously are combined. The following description for the cyanidation can be used for both alternatives equivalently.

Expediently, A is a bond or is selected from linear or branched Ci_-5 alkylene and C-6-10 arylene groups. Preferably A is a bond or a linear d_-5 alkylene group. Most preferably, A is a bond or a methylene or ethylene group. In another preferred embodiment A is a C-6-10 arylene group, more preferably is phenylene group, even more preferably a p-phenylene group.

In a preferred embodiment at least 50% of the total amount of HCN used in the process and at least 10% of the total amount of the compound of formula II, wherein A, Hal and R are as defined above, used in the process are fed to the reaction zone as a premix comprising HCN and said compound of formula II. More preferably HCN is only used as a premix comprising HCN and at least 10% of the total amount of the compound of formula II.

As outlined above, cyanidation of chloroacetic acid ethyl ester (compound of formula II, wherein Hal is chloro, A is a bond, and R is ethyl) with HCN major and well-known side products are 2-cyano succinic acid diethyl ester (C_gH₁₃NO₄, [10359-15-6], DECS) and triethyl 2-cyanopropane-1 ,2,3-tricarboxylate (C₁₃H₁₉NO₆, [20822-61 -1 ],

TECP). Within the cyanidation reaction these compounds and other polycyanidated compounds and polymeric HCN compounds form a brown to black sticky residue, which not only reduces yields, but also form clogging deposits in the reactors and reactor tubes, which are difficult to remove from the final product. Using HCN in a premix with the compound of formula II and the instant process has the beneficial effect of higher yields, better selectivity and less formation of side products compared to the process as outlined for example in EP-999206-A. Especially the formation of dark to black polymeric side products is reduced compared to the state of the art.

The premix of HCN and compound of formula II can be provided in different ways to the reaction mixture. In batch or semi-batch reaction the premix can be added as such and/or be present in the reactor at least in part before addition of the base. In a tubular reactor such as a static mixer the premix can also added as such or also be obtained in-situ in a first section of the reactor by feeding HCN and the compound of formula II before the addition of the base to the feed stream at a second section of the tubular reactor. Especially in a tubular reactor the premix and the base can be fed in fractions at different inlet ports along the reaction tube and/or in intervals to reduce high concentrations in one volume element at a certain time. A suitable tubular reactor to carry out the cyanidation reaction as defined above can also be a microreactor. Preferably, by carrying out the reaction in a microreactor, the addition of the base and the premix is carried out using a multi-injection micro reactor as provided for example in WO/2007/1 12945.

Furthermore the addition of HCN as premix with the compound of formula II together with the instant process increases yield and selectivity.

Expediently, the premix comprises at least 15% of the total amount of compound of formula II used in the process, preferably at least 20%, and more preferably at least 25%. In another preferred embodiment the premix comprises between 20 to 80% of the total amount of the compound of formula II, wherein A, Hal and R are as defined above, used in the process. Preferably the premix comprises up to 60% of the total amount of the compound of formula II, wherein A, Hal and R are as defined above, more preferably up to 50%.

Also expediently, between 25 to 45% of the total amount of the compound of formula II, wherein A, Hal and R are as defined above, is fed within the premix.

In a preferred embodiment the first base is an organic base. Preferably said first base is a primary, secondary or tertiary amine base, more preferably is selected from the group consisting of ammonia, linear, branched or cyclic tertiary alkylamines, most preferably is a Ci-3-trialkylamine.

In a further preferred embodiment the first base is an alkylamine selected from the group consisting of methylamine, ethylamine, propylamine, cyclopentylamine, cyclohexylamine, dimethylamine, diethylamine, dipropylamine, trimethylamine, triethylamine, tripropylamine, ethyldimethylamine, diethyl-isopropylamine and ethyl- di-isopropylamine.

In the process as outlined above, a preferred molar ratio of the first base to the compound of formula II, wherein A, Hal and R are as defined above, is in the range from 1 :1 to 1 :5, preferably from 1 :2 to 1 :4. Molar ratio in the examples was about 1 :3. Preferably, the ratio of total molar amount of HCN fed to the reaction mixture and total molar amount of the first base fed to the reaction mixture is at least 10:9, i.e. the total molar amount of HCN fed to the reaction mixture, at any time, is always higher than the total molar amount of said first base fed to the reaction mixture.

Expediently, the molar total amount of the first base refers to its valency, i.e. 1 mole of a divalent base such as Na₂CO3 correlates to 2 mole of a monovalent base such as triethylamine. Depending on dissociation constants of the base in view of HCN usually 1 mole of a divalent base, even a trivalent base, correlates to a range from 1 to 2 mole of a monovalent base. Typically, the molar ratio of HCN to the first base in the reaction mixture is in the range of from 10:9 to 10:5, more preferably of from 10:9 to 10:6. A molar ratio of HCN to the first base of 10:5 is also possible but results in increased reaction times. HCN preferably is added to the halocarboxylic acid alkyl ester in liquid form but can also be added by feeding it in gaseous form or in the form of a liquid/gas mixture.

To further enhance selectivity, the process may performed in the presence of a catalyst, said catalyst being obtained by mixing a second base, said second base having a pK_a of 8 or higher, and an acid, said acid having a pKa of 5 or lower.

Thus, the catalyst corresponds to a salt of a conjugate base and a conjugate acid having the pK_a's mentioned above. In case of polybasic acids such as oxalic acid, citric acid, sulfuric acid or phosphoric acid, only the first deprotonation step needs to fulfill the requirement of having a pK_a 5 or lower. In a preferred embodiment the second base has a pK_a 9 or higher, even more preferably a pK_a 9.5 and higher.

Expediently the second base is selected from the group consisting of amine bases and phosphonium bases. More preferably the second base is an amine base.

Adding the catalyst mentioned above further increases the yield and selectivity already achieved by supplying a premix comprising HCN in a compound of formula II as mentioned above. The catalyst can be added as such or is formed in-situ in the reaction mixture after as isolated conjugate acid and conjugate base. Both

applications can be mixed, by partly addition of neat or suspended catalyst and addition of said acid and said second base. Of course, also different catalysts can be used. To keep the reaction system and down-stream chemistry simple, addition of only one catalyst is preferred.

Expediently, the catalyst, or its respective starting compounds, is fed in neat form or in a mixture with the compound of formula II. In case of addition of the acid and the second base separately to obtain the catalyst in situ, preferably the catalyst formation is carried out directly in the feed stream comprising the compound of formula II. In semi-batch reaction preferably the catalyst is present before addition of the premix and the first base.

The acid can be an inorganic or organic acid. Preferably the acid is selected from the group consisting of formic acid, acetic acid, chloro acetic acid, dichloroacetic acid, trichloroacetic acid, fluoroacetic acid, trifluoroacetic acid, benzoic acid, hydrogen fluoride, hydrogen chloride, hydrogen bromide, hydrogen iodide, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, phosphoric acid, phosphorous acid and pyrophosphoric acid.

More preferably the acid is hydrogen chloride.

In a preferred embodiment the catalyst is a hydro halide salt of a tertiary alkylamine (ammonium halide catalyst), selected from methylammonium halides,

dimethylammonium halides, trimethylammonium halides, ethylammonium halides, diethylammonium halides, triethylammonium halides, propylammonium halides, dipropylammonium halides, tripropylammonium halides, isopropylammonium halides, diisopropylammonium halides, tri-isopropylammonium halides,

diisopropylethylammunium halides, ethyldimethylammonium halides, diethyl-iso- propylammonium halides, tributylammonium halides, trihexylammonium halides, tri- (2-ethyl-hexyl)ammonium halides, cyclopentyldimethylammonium halides,

cylohexyldimethylammonium halides, and ethyl-di-cyclohexylammonium halides.

Even more preferred the ammonium halide catalyst is an ammonium chloride catalyst. In another preferred embodiment the catalyst is a phosphonium salt selected from the group consisting of quaternary phoshonium salts, such as triaklylphosphonium halides, dialkylarylphosphonium halides, alkyldiaryl phoshonium halides,

triarylphosphonium halides. Even more preferred the phosphonium halide catalyst is a phosphonium chloride catalyst. Expediently, the first and the second base are the same.

The present cyanidation process can be carried out in semi-batch or continuous mode.

In semi-batch mode part of the compound of formula II and at least an initial amount of the catalyst is charged to the reactor, and the first base and a premix comprising hydrogen cyanide and the compound of formula II are fed separately to the reactor. By carrying out the cyanidation in semi-batch mode the molar ratio of the catalyst to the first base preferably is in the range of 0.01 :1 to 0.3:1 .

More preferably the continuous mode is carried out in a continuous reactor selected from the group consisting of continuously stirred tank reactors, a cascade of continuously stirred tank reactors, tubular reactors, micro reactors and mixtures thereof, comprising at least one feed stream.

By carrying out the cyanidation in continuous mode the compound of formula II is provided in the at least one feed stream.

Preferably, the compound of formula II is provided in at least one feed stream.

Also, by carrying out the cyanidation in continuous mode, the feed stream comprises the compound of formula II and the catalyst, while the base and the premix are independently (separately or collectively) fed to the reactor in at least one side stream. Expediently, in the present cyanidation reaction, regardless of reaction mode, the molar ratio of the catalyst present in the feed stream to the first base fed in at least one side stream is in the range of 0.01 :1 to 0.3:1 . Preferably, in both semi-batch or continuous mode, the molar ratio of the catalyst to the first base fed to the reactor is at least 0.05:1 . In another preferred embodiment, the molar ratio of the catalyst to the first base is at least 0.1 :1 .

In a preferred embodiment, in both semi-batch or continuous mode, the molar ratio of the catalyst to the first base fed to the reactor is 0.2:1 or lower, more preferred is 0.15:1 or lower.

Expediently, the process as outlined above is carried out without additional solvent. Also expediently, the reactants can be added continuously or in appropriate portions. As outlined above, the present cyanidation is suited to be used as continuous process in connection with esterification of a compound of formula III with a compound of formula IV to obtain compound of formula II, which can be used as such or further reacted with HCN to obtain the compound of formula I.

Thus, in the following we provide a process and equipment for the preparation of the compound of formula II. Provided is a process for preparing a compound (halocarboxylic acid alkyl ester) of formula

Hal-CH₂-A-C(O)-OR II, wherein Hal is a halogen atom selected from F, CI, Br and I, wherein A denotes a bond or a divalent spacer selected from alkylene and arylene groups, and wherein R is a Ci_-4 alkyl group, by reacting a compound (halocarboxylic acid) of formula

Hal-CH₂-A-C(O)-OH III, wherein Hal and A are as defined above,

with a compound (alcohol) of formula

ROH IV,

wherein R is as defined above, in a reactive distillation column comprising a reaction zone, a separation zone and, optionally, an extraction zone, wherein said process comprises:

(a) feeding said compound of formula IV into an reaction zone containing a heterogeneous catalyst and contacting said heterogeneous catalyst,

(b) feeding said compound of formula III above the reaction zone,

(c) removing said compound of formula II below the reaction zone of said reactive distillation column. Preferably the process is carried in a reactive distillation column, comprising a separation zone being located above the reaction zone, said separation zone providing a mass transfer surface, and optionally reactive distillation column further comprising, an extraction zone providing an additional mass transfer surface, said extraction zone being located between said reaction zone and said separation zone. In a preferred embodiment the divalent spacer is selected from the group consisting of linear or branched Ci_-5 alkylene and C6-io arylene groups, preferably is a linear Ci-5 alkylene group. Preferably, the compound (halocarboxylic acid) of formula III is fed to the process below the separation zone and above the reaction zone, where the compound of formula III enters the reaction zone and reacts with the compound of formula IV to form the product of formula II (halocarboxylic acid alkyl ester). Conveniently, the compound of formula III is introduced in a liquid form, optionally heated and/or optionally in the presence of an inert solvent. In a preferred embodiment, for example in the reaction of 2-chloroacetic acid (compound of formula III, wherein Hal is chloro and A is a bond) and ethanol (compound of formula IV, wherein R is ethyl), the molar ratio of halocarboxylic acid to alcohol fed into the column is in the range of from 1 :1 to 1 :5, preferably of from 1 :1 to 1 :3, and more preferably of from 1 :1 .5 to 1 :2.

In a preferred embodiment the compound of formula III is a C2-5 halocarboxylic acid, more preferably a C2_-4 halocarboxylic acid. Examples of useful halocarboxylic acids are 2-haloacetic acids, 2- or 3-halopropionic acids, 2-, 3- or 4-halobutyric acids, 4-haloisobutyric acids, and 2-, 3-, 4- or 5-halopentanoic acids. Typically, the halocarboxylic acid is a monochloro- or monobromocarboxylic acid, in particular a monochlorocarboxylic acid.

In a further preferred embodiment, the compound of formula III is selected from 2-chloroacetic acid, 2- or 3-chloropropionic acid, 2-, 3- or 4-chlorobutyric acid and 2-, 3-, 4- or 5-chloropentanoic acid, wherein 2-chloroacetic acid and 2- or 3-chloropropionic acid are particularly preferred. Most preferably the compound of formula III is 2-chloroacetic acid.

Expediently, the compound of formula IV is a linear or branched Ci- alkyl alcohol selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, sec-butanol, isobutanol and te/t-butanol. Most preferably, the compound of formula IV is selected from methanol, ethanol and isopropyl alcohol.

Also preferably, the compound of formula IV (alcohol) is fed into the reaction distillation column in the range from the lower half to the end of the reaction zone.

More preferably the compound of formula IV is fed into the reaction distillation column in the range between the lower half and the lower third of the reaction zone. In a further embodiment the compound of formula IV is introduced as a water/alcohol mixture. Preferably an alcohol/water mixture feed approx. contains the respective azeotropic alcohol/water ratio. The alcohol or the alcohol/water feed mixture may or may not be heated. A pre-heated alcohol or alcohol/water feed is preferred. In a further embodiment, in the present process at standard conditions (1 bar) the boiling point of the alcohol (compound of formula IV) is lower, preferably at least 10 °C lower, than the boiling point of the corresponding product of formula II

(halocarboxylic acid alkyl ester) at standard conditions (1 bar atmospheric pressure). Thus the boiling point difference is at least 10 °C at standard conditions. More preferably, the boiling point difference at standard conditions is 20 °C or more, even more preferably 30 °C or more, and most preferably more than 40 °C. According to a further embodiment of the invention, the temperature in the reactive distillation column is controlled to maintain the liquid mixture in the bottom part of the distillation column at a temperature of at least about 10 °C above the boiling temperature of the alcohol, i.e., the boiling point of the alcohol at the respective pressure in the distillation column.

Unreacted halocarboxylic acid and halocarboxylic acid alkyi ester resulting from the reaction between halocarboxylic acid and alcohol drop to the bottom of the column forming part of the bottom stream in the column. The reactive distillation column is heated at a temperature in a range between about 20 °C below to the boiling temperature at operating pressure of said halocarboxylic acid alkyi ester. More preferably, the temperature is controlled to maintain the reaction mixture within a temperature range of from about 10 °C below boiling temperature to boiling temperature of the alkyi halocarboxylic acid alkyi ester at standard conditions. Most preferably, the temperature of the reaction mixture in the distillation column corresponds to the boiling temperature of the halocarboxylic acid alkyi ester produced. In the case of the reaction of 2-chloroacetic acid with ethanol (boiling point 78 °C), expediently the temperature at the bottom of the column is maintained the boiling temperature of ethyl chloroacetate of between 125 to 145 °C at standard conditions, preferably at about 145 °C.

Advantageously the process of the invention is carried out at ambient pressure.

Also provided is a process, wherein the compound of formula II obtained in the first reaction process (reactive distillation), optionally after further rectification, is directly fed in the second reaction process (cyanidation). Withdrawal of the compound of formula II from the reactive distillation column can be carried out, either partially or completely, by (a) removing the gaseous phase between the reaction zone and the reboiler and/or (b) removing the condensed phase from the reboiler.

Apparatus for carrying out the inventive reaction.

We also provide an apparatus (reactive distillation column) suitable for carrying out the above mentioned process of preparing the compound of formula II,

comprising:

(i) a reaction zone containing a heterogeneous esterification catalyst,

(ii) a separation zone providing a mass transfer surface and being located above said reaction zone, and, optionally

(iii) an extraction zone providing an additional mass transfer surface and being located between said reaction zone and said separation zone

(iv) at least one feed for supplying a compound (halocarboxylic acid) of formula

Hal-CH₂-A-C(O)-OH III wherein Hal and A are as defined above, said feed for supplying the compound of formula III being located below the separation zone and above the reaction zone (V) at least one feed for supplying a compound (alcohol) of formula

ROH IV

wherein R is as defined above, said feed for supplying the compound of formula IV being located within the reaction zone

(vi) means for removing the compound of formula II below the reaction zone of said reactive distillation column.

Expediently, the temperature of the bottom liquids are controlled such that it is not more than 20 °C below the boiling temperature of the compound of formula II under operating pressure.

The reactive distillation may be a glass column or a metal column, for example made from a nickel-based alloy such as Hastelloy, such as a Hastelloy C22 column. The column comprises at least a reaction zone and a separation zone located above said reaction zone.

The reaction zone, i.e., the zone where the compound of formula III reacts with the compound of formula IV, contains a heterogeneous catalyst, preferably a

heterogeneous esterification catalyst. A heterogeneous catalyst does need not be extracted from the bottom product and thus facilitates the process. The

heterogeneous catalyst may be a solid or solidified catalyst, i.e., a catalyst solidified by coating the catalytically active material on an inert solid support. Preferably, the catalyst is an acidic catalyst, and more preferably is a solid or solidified body selected from acidic clays, acidic zeolites, acidic ion exchange resins, and heteropoly acids. In a preferred embodiment the heterogeneous catalyst tends to show no or minimal leaching under the reaction conditions. An example of preferred acidic clays is Fe³⁺-montmorillonite.

Examples of preferred acidic zeolites are H-ZSM-5, HY or H-Beta.

Examples of preferred acidic ion exchange resins are acidic resins available under

TM TM

the trade name Amberlyst , in particular Amberlyst resins selected from the group

TM TM TM TM

consisting of Amberlyst 131 , Amberlyst 15, Amberlyst 16, Amberlyst 31 ,

TM TM TM TM TM

Amberlyst 33, Amberlyst 35, Amberlyst 36, Amberlyst 39, Amberlyst 40,

TM TM TM

and Amberlyst 70. Most preferably the acidic Amberlyst resin is Amberlyst 36.

Solid heteropoly acids comprise solid and solidified heteropoly acids, i.e., heteropoly acids coated on an inert carrier. Examples of preferred heteropoly acids are tungstates (wolframates) or molybdates, for example those of formulae H Xⁿ⁺Mi₂O₄o, wherein X is Si or Ge and M is Mo or W, H₃Xⁿ⁺Mi₂O ₀, wherein X is P or As and M is Mo or W, and Η₆Χ2Μι₈Ο₆2, wherein X is P or As and M is Mo or W. Preferred heteropoly acids are, tungstates, wherein M is W. Preferred tungstates are selected from the group consisting of preyssler heteropoly acid catalysts such as Hi₄[NaP₅W₃oOno]; Keggin structured heteropoly acids such as H₃[PWi₂O₄o], H₄[SiWi₂O₄₀]; H₅[PWiiTiO₄₀], H₅[PW ZrO₄o], and H₃[PWiiThO₃9] ; and Dawson structured heteropoly acids such as a-H₆[P2Wi₈O62] , H₆[P2W₂iO₇i] (H₂O)₃,

H₆[As₂W₂i O69] (H₂O) and H₂₁ [B₃W₃₉Oi₃₂]. Each heteropoly acid optionally can be used with or without silica (SiO₂), niobium pentoxide (Nb₂O₃), zirconia (ZrO₂) or titania (TiO₂) carrier, such as H₃[PW₁₂O₄₀], Ho.5[Cs₂.₅PW₁₂O₄o], H₄[SiW₁₂O₄₀], 15% H₃[PW₁₂O₄₀]/Nb₂O₅, 15% H₃[PW₁₂O₄₀]/ZrO₂ and 15% H₃[PW₁₂O₄₀]/TiO₂. The packing of the catalyst is designed to enable a reaction in a liquid film on the catalyst. Thus, the catalyst packing comprises enough space to establish a

continuous vapour phase in the reactive distillation column. Preferably the catalyst is comprised in compartments, for example in woven metal fabric bags, optionally further stacked or compiled in cages, for example in a structured catalytic packing such as Katapak™ SP, wherein the catalyst is located in the Katapak™-SP packing elements. According to a further preferred embodiment, the catalytic packing is divided into at least two sections to allow easy feeding of the starting compound feeds between said sections.

Preferably, the separation zone contains a mass transfer surface.

A mass transfer surface to be used in the present invention can be for example a set of, optionally corrugated, metal plates column plates, a suitable particle filling providing a high surface, or said mass transfer surface can be provided by a porous or spongiform material. The material of said mass transfer surface preferably is heat resistant and chemically inert under the reaction conditions such as glass, ceramics, high temperature resistant polymer or metal, such as stainless steel. Said particles providing said mass transfer surface, can be for example coarsely broken or regularly shaped, filamentous pieces, such as Raschig rings, Pall rings, glass or metal fibers. In one embodiment the particles might be packed in cages or woven metal or glass fiber fabric sacs which facilitate handling such as packing or exchanging the material. In another embodiment the filling can be placed as an accretion on a column plate. In a preferred embodiment the body is a metal packing, comprising filamentous metal, optionally filled in cages or woven metal fabric sacs. In the separation zone ester and acid condenses on the filling material and thus essentially do not leave the distillation column over the column head.

Optionally, the reactive distillation column may also comprise an extraction zone located between the reaction zone and the separation zone. The optional extraction zone also contains a mass transfer surface, which may be the same or different from that of the separation zone, to prevent formation of an ester-water heteroazeotrope.

Each of the reaction zone, the separation zone and the extraction zone can be divided into separated layers of adequate filling.

Starting the reaction in the reactive distillation column is carried out according to state of the art procedures.

In a preferred embodiment, the column is divided into a portion comprising a reaction zone containing the heterogeneous catalyst and a portion comprising a separation zone containing a mass transfer surface. The reaction zone is located in the lower part of the column and the separation zone is located above said reaction zone. An optional extraction zone, which preferably also contains a mass transfer surface, is located between the separation zone and the reaction zone. The separation zone can comprise bubble trays, bubble cap trays or sieve trays as mass transfer surface or further comprise material as described above. Preferably, the body of the reactive distillation column comprises columns with different inner diameters so that the portion of the column comprising reaction zone has a wider diameter than the portion comprising the separation zone and optional extraction zone. For example, for reacting about 300 to 350 Kg/h halocarboxylic acid (compound of formula III, wherein A is a bond and Hal is chloro) suitable diameters of reaction zone and separation zone may be about 30 cm and 10 cm, respectively. Different sized portions of the column are particularly useful for the preparation of 2-chloroacetic acid alkyl esters. In any case, a narrower diameter of the separation zone has the advantage of increased contact between the liquid and vapour phase.

Typically the compound of formula III is fed into the reactive distillation column through an, optionally heated, inlet port located immediately below the separation zone and above the reaction zone. Within the column the compound of formula III predominantly moves down to reaction zone and reacts with the compound of formula IV, which is fed through an, optionally heated, inlet into the reaction zone where it is vapourized. Preferably, the feed of the compound of formula IV enters the reactive distillation column as low as possible while it should be avoided that the compound of formula directly enters the liquid in the bottom. In an industrial size facility, for example for esterification of 2-chloroacetic acid with ethanol, the height of the catalyst filled reaction zone preferably has a total length of about 6 to 10 m at a maximum liquid throughput of about 15 m³/m²h, with a height of the catalyst packing below the feed of the compound of formula IV being about 1 to 2 m and a height of the catalyst packing above the feed of the compound of formula IV being about 5 to 8 m. The separation zone typically has a length of about 2 to 3 m.

The compound of formula II resulting from the reaction of compound of formula III and compound of formula IV, and optionally, unreacted compound of formula III forms the bottom stream which is heated by a heating system connected to the bottom of the column. Regarding the filling of the column bottom, the heating elements should be sufficiently media surrounded to prevent decomposition of the organic compounds. Preferably the heating system is designed as a thermosyphon reboiler (also known as calandrias, i.e. an evaporator with natural circulation) or a kettle reboiler (i.e. a forced circulation reboiler). Other reboiler types are also possible. Thermosyphon reboilers have the advantage of less maintenance compared to other reboilers. Thermosyphon and kettle reboilers reduce thermal strain on the product compared to direct heating such as, for example, direct heating of a distillation bladder. The heating system provides the thermal energy to evaporate the mixture in the column bottom and provides a constant pressure of vapour in the column. The reactive distillation column is heated at the bottom and optionally also comprises individually controllable means for adjusting the temperature along the column.

The compound of formula IV, having a lower boiling then the product of formula II, is distributed in the reaction zone of the reactive distillation column. Unreacted compound of formula IV further enters the optional extraction zone and finally the separation zone. Finally the compound of formula IV reaches the column head, where it leaves the process in a mixture together with water, which at least partially is formed during the reaction, as the main component of the head stream. Said mixture head stream comprising water and the compound of formula IV exits the column and is fed to a condenser, to condense the head stream. A fraction of the condensed head stream is reintroduced into the column head as a reflux stream. The remaining fraction of the condensed head stream is withdrawn as a withdrawal stream and may be further processed to recycle the compound of formula IV and/or water to the process. In a preferred embodiment, a fraction of water of the condensed head stream is removed in a subsequent column and the recovered compound of formula IV, optionally as an mixture of water and the compound of formula IV, is recycled to the reaction zone. The ratio of the split between reflux stream and withdrawal stream expediently is in a range of from 0.4:1 to 2:1 , preferably is in the range of from 0.6:1 to 1 .5:1 . In case of the esterification of 2-chloroacetic acid with ethanol, for example, the weight ratio most preferably is about 0.8:1 . In that system the reflux stream mainly consists of water and ethanol and comprises only minor amounts of the starting acid and the ester product of formula II.

At the top of reaction zone, a heteroazeotrope of water with compound of formula II may occur which can be prevented by inserting the optional extraction zone. In said optional extraction zone, the compound of formula II and the compound of formula III are condensed and are extracted from the vapour phase and reintroduced into the column by the respective feed. In an 2-chloroacetic acid/ethanol system an extraction zone is not necessary and a simple separation zone is likely sufficient to effectively reduce the amount of the compounds of formula II and III to prevent them to escape the reactive distillation column as over head stream. The remaining head stream of the column comprises mainly water and alcohol.

The bottom stream, which optionally is essentially free of water and the compound of formula IV and thus mainly comprises the compound of formula II and optionally some unreacted compound of formula III and/or high boiling by-products, exits the reactive distillation column at the bottom of the column. The molar ratio between compound of formula II (halocarboxylic acid alkyl ester) to compound of formula III (halocarboxylic acid) can be increased with the length of the column. Preferably, the column length is sufficient to reduce the amount of remaining the compound of formula III in the lower part of the column to nearly zero. The bottom stream exiting the column may be divided into a reboiler stream and a crude stream of the compound of formula II. The reboiler stream is heated in an external heating system and is reintroduced into the column through a line either by natural or by forced circulation. The stream of crude compound of formula II is subjected to further downstream processing through line. The crude product stream preferably is withdrawn from the column in a manner not to negatively affect the circulation stream.

At the top of the reactive distillation column, an mixture mainly comprising the compound of formula IV and water, is withdrawn through and fed to a further rectification column, for example a stainless steel column operated at ambient pressure, in order to recycle the compound of formula IV to the process. The bottom residue of the rectification column, after purification of the compound of formula II, can be disposed. The crude product of compound of formula II, mainly comprising the desired ester and some unreacted compound of formula III is withdrawn from the bottom of the rectification column and is charged to a further rectification column, for example a stainless steel column preferably operated under vacuum conditions, for example at a pressure from 300 to 500 mbar, for further product purification. The fraction containing for example unreacted halocarbocylic acid, by-products and impurities, such as di- or trihalogenated acids and respective esters, can be removed through while the purified compound of formula II is removed from the head of the column as an end product or as an intermediate for use in further reactions.

Depending on the residual amount of unreacted compound of formula III, optionally further rectification means as known to the skilled person, such as flash evaporator or further distillation columns, can be introduced in the downstream processing. While esterification is an equilibrium reaction in which the compound of formula III cannot be fully converted into the respective compound of formula II, it has been found that the process of the invention using reactive distillation allows the

equilibrium to be shifted towards the formation of the product. Therefore, a high conversion preferably at least 80%, particularly preferred at least 90% regarding the halocarboxylic acid can be obtained. In a further preferred embodiment, depending on the length of the active part of the reactive distillation column and the product flow, a conversion up to >99% can be reached. Moreover in the present reactive distillation the formation of by-products is significantly reduced. In the substantial absence of water and compound of formula IV in the raw product stream the complexity of the working-up procedure in the reactive distillation is reduced compared to solvent based esterification. Less equipment is required and less cost is foreseen due to the equipment. The present reaction set up uses the advantage of solvent based reaction, reaction in liquid phase, i.e. in the liquid film established around the catalyst bodies, and the advantage of good separation of low and high boilers in gaseous reaction and also avoids emulsion formation which often occurs in solvent

esterification.

The use of a heterogeneous catalyst eliminates the separation requirement in the case of a homogeneous catalyst in batch or continuous reaction. Due to the formation and presence of azeotropes, the separation of the reaction mixture from water and/or alcohol is very difficult in the case of the conventional procedure, where the ester is withdrawn or condensed from the vapour phase. With the present reactive distillation including withdrawal of essentially water free compound of formula II, optionally together with some compound of formula III, from the bottom, the problem of azeotrope separation can be overcome. Separation of compound of formula III and compound of formula II by distillation is difficult in the presence of water due to formation of azeotropes, especially in the additional presence of compound of formula III. The desired compound of formula II can be withdrawn at the bottom of the column although it has a lower boiling point than the corresponding compound of formula II which was initially fed to the column. Compared to batch mode the average residence time can be roughly shortened by a factor of about 2, i.e. the time for reacting the same acid amount in continuous column mode including separation from catalyst can be shortened from about 120 min to about 50 to 60 min.

In most cases it is only necessary to heat the column bottom and due to the moderate temperatures, the instant esterification process saves energy compared to the state of the art processes with head stream withdrawal

Since the used compound of formula III, such as 2-chloroacetic acid, always has a higher boiling point than the compound of formula II, such as ethyl 2-chloroacetate, the boiling point of the compound of formula II is the measure to control the bottom temperature of the reactive distillation column, causing the compound of formula III to move down the column and to pass the reaction zone where the compound of formula II, such as ethyl 2-chloroacetate, is formed. Only a minor amount of the compound of formula III can go up the column together with water and the compound of formula IV vapour to pass the separation zone. Even less compound of formula III will leave the column over head. This simplifies work up and recycling of unreacted ethanol and raises the conversion of the acid in the process. Examples:

Use of a HCN/compound of fornnula ll-premix is not sufficient as sole means to obtain best results. The advantage of the instant feeding strategy, especially together with using the premix, is demonstrated by instant examples 1 to 7 in view of comparative examples 3 and 4. Comparison examples 1 and 2 have been carried out following EP 0999206. An already improved process, also using a premix comprising HCN and a compound of formula II, as presented in comparison examples 3 and 4, leads to much better results in view of the state of the art. Further amending the addition process resulted in the process according to claims 1 to 14.

Comparison example 1 :

2-chloro ethyl acetate (CIEt, compound of formula II, wherein Hal is chlorine, A is a bond and R is ethyl, 80 g, 650 mmol) and tetrabutylammonium bromide (TBAB 500 mg, 1 mmol) as catalyst in dichloromethane (141 ml_) were placed in a vessel. To the stirred mixture an aqueous solution of sodium cyanide (38.4 g, 780 mmol in 70 mL water) was added dropwise over 1 h at room temperature. After complete addition of the solution the reaction mixture was stirred for further 3 h at room temperature. After stopping stirring and reaching phase separation the organic phase was removed and washed with water. 63.9% conversion was reached based on CIEt. Selectivity was 62.3% for the main product 2-cyano ethyl acetate (CNEt, compound of formula I, wherein A is a bond and R is ethyl). Selectivity of side products were 14.7% for 2-cyano succinic acid diethyl ester (DECS) and 7.6% for triethyl

2-cyanopropane-1 ,2,3-tricarboxylate (TECS), respectively. Yield was 44.0% for CNEt, 10.4% for DECS and 5.4% for TECS, respectively. In the reaction a remarkable amount of esters were hydrolyzed in the aqueous mixture and thus ethanol (EtOH) was a further major side product of approx. 10% yield.

Comparison example 2:

Na₂CO₃ (985, 70.6 g, 650 mmol) and dimethylacetamide (308 g) were placed in a vessel. The mixture was heated under stirring to 50 °C. To the mixture a premix consisting of 2-chloro ethyl acetate (80 g, 650 mmol) and HCN (70.6 g, 2.61 mol) was added within 1 h. After complete addition of the premix the reaction mixture was stirred for further 2 h at that temperature. The reaction mixture was cooled to room temperature and the solid product filtered and washed with dimethylacetamide. The filtrate was analyzed. During the reaction 90% conversion was reached. CNEt was formed with a selectivity of 87.2% and a yield of 78.5%.

Comparison example 3:

2-chloro ethyl acetate (230.0 g, 1880 mmol) and HCN (50.73 g, 1880 mmol) were placed in a vessel and warmed to 30 °C. To the stirred mixture triethylamine (95.9 g, 940 mmol) was added over 1 h. After complete addition of triethylamine the brown suspension was kept under stirring for further 1 h and then cooled to 20 °C. The reaction mixture was removed from the vessel and filtered. The filter cake was washed with acetonitrile (100 mL). The organic phase was dried and analyzed. CNEt was formed with a selectivity of 84.8% and a yield of 88.0 %. The filtrate also comprises approx. 8.5 wt-% of polymeric HCN side products. The amount of said polymeric HCN side products have been determined by removing all low molecular compounds by distillation and further drying the distillation residue in a vacuum oven. Comparison example 4:

2-chloro ethyl acetate (180.0 g, 1471 mmol) was placed in a vessel and brought to 20 °C. A premix of CIEt (50.0 g, 409 mmol) and HCN (50.73 g, 1880 mmol) was prepared and added within 70 min to the vessel. 10 min after start of the premix addition triethylamine (95.9 g, 940 mmol) was added within 60 min. After complete addition of triethylamine the brown suspension was kept under stirring for further 1 h. Water (100 mL) was added to the reaction mixture for extraction of water soluble compounds. After phase separation the organic phase comprising the products was analyzed. CNEt was formed with a selectivity of 76.0% and a yield of 81 .0%. The organic phase also comprises approx. 8.5 wt-% of polymeric HCN-side products.

Example 1 :

2-chloro ethyl acetate (CIEt, compound of formula II, wherein Hal is chlorine, A is a bond and R is ethyl, 178.06 g, 1455 mmol) was placed in a vessel and warmed to 15 °C. A premix of CIEt (1 1 1 .94 g, 915 mmol) and HCN (44.77 g, 1660 mmol) was prepared and added within 100 min to the vessel. In parallel to the premix addition triethylamine (80.5 , 980 mmol) addition was started but completed within 70 min. After complete premix addition the reaction mixture was kept under stirring for further 2 h. Water (108 mL) was added to the reaction mixture for extraction of water soluble compounds. After phase separation the organic phase comprising the products was analyzed. Ethyl cyanoacetate (CNEt, compound of formula I, wherein A is a bond and R is ethyl) was formed with a selectivity of nearly 100% and a yield of 94.2%. No insoluble polymeric HCN-side products could be detected in the organic phase. Example 2:

2-chloro ethyl acetate (174.18 g, 1421 mmol) was placed in a vessel and warmed to 15 °C. A premix of CIEt (75.82 g, 618 mmol) and HCN (30.33 g, 1 120 mmol) was prepared and added within 100 min to the vessel. In parallel to the premix addition triethylamine (69.4 g, 680 mmol) addition was started, but completed within 70 min. After complete premix addition the reaction mixture was kept under stirring for further 2 h. Water (91 .9 ml_) was added to the reaction mixture for extraction of water soluble compounds. After phase separation the organic phase comprising the products was analyzed. CNEt was formed with a selectivity of 93.3% and a yield of 93.1 %. No insoluble polymeric HCN-side products could be detected in the organic phase.

Example 3:

2-chloro ethyl acetate (167.29 g, 1365 mmol) was placed in a vessel and brought to 15 °C. A premix of CIEt (82.71 g, 675 mmol) and HCN (33.1 g, 1222 mmol) was prepared and added within 100 min to the vessel. In parallel to the premix addition triethylamine (69.4 , 680 mmol) was added, but only within 70 min. After complete premix addition the reaction mixture was kept under stirring for further 2 h. Water (91 .9 ml_) was added to the reaction mixture for extraction of water soluble

compounds. After phase separation the organic phase comprising the products was analyzed. CNEt was formed with a selectivity of 95.1 % and a yield of 91 .2%. No polymeric HCN-side products could be detected in the organic phase.

Example 4:

2-chloro ethyl acetate (167.3 g, 1365 mmol) and triethylamine hydrochloride (14.0 g, 100 mmol) were placed in a vessel and brought to 40 °C. A premix of CIEt (82.7 g, 675 mmol) and HCN (33.1 g, 1222 mmol) was prepared and added within 40 min to the vessel. In parallel to the premix addition triethylamine (69.4 g, 680 mmol) was added, but only within 30 min. After complete premix addition the reaction mixture was kept under stirring for further 1 h. Water (91 .9 ml_) was added to the reaction mixture for extraction of water soluble compounds. After phase separation the organic phase comprising the products was analyzed. CNEt was formed with a selectivity of 96.6% and a yield of 87.8%. No polymeric HCN-side products could be detected in the organic phase.

Example 5:

2-chloro ethyl acetate (153.5 g, 1253 mmol) and triethylamine hydrochloride (14.0 g, 100 mmol) were placed in a vessel and brought to 15 °C. A premix of CIEt (96.5 g, 787 mmol) and HCN (38.6 g, 1430 mmol) was prepared and added within 60 min to the vessel. In parallel to the premix addition triethylamine (69.4 g, 680 mmol) was added, but only within 50 min. After complete addition of the premix the suspension of the reaction mixture was kept under stirring for further 1 h. Water (93.8 ml_ ml_) was added to the reaction mixture for extraction of water soluble compounds. After phase separation the organic phase comprising the products was analyzed. CNEt was formed with a selectivity of 96.8% and a yield of 90.7%. No polymeric HCN-side products could be detected in the organic phase.

Example 6:

A premix of pure HCN (4.05 kg) and ethyl chloroacetate (10.2 kg) was prepared and portioned into three equal portions and placed in tanks. To carry out the reaction in continuous mode a cascade of 4 continuously stirred tank reactors (CSTR) with separate temperature control was used. To control mass flow, all reactors and tanks have been placed on scales, wherein signals from the scales were used as input signal for triggering the pumping system. For adjustment of the residence times in the 4 CTSR's the mass limits in the reactors were set to be 1 .30, 1 .65, 1 .80 and 5.30 kg in reactors 1 to 4, respectively.

The premix was dosed with following feed rates: Reactor 1 : 1 .901 kg/h of premix and 0.304 kg/h of first base; Reactor 2: 0.314 kg/h premix, 0.304 kg/h of first base and 2.20 kg/h of reactor 1 ; Reactor 3: 0.314 kg/h of premix and 2.80 kg/h of reactor 2; Reactor 4: 3.10 kg/h of reactor 3. All reactors were temperature adjusted to 25 °C and stirred at 300 rpm.

The feeds to reactors 2 to 4 were started after reaching the mass limit of the predecessor vessel. After about 3.5 h the 4 reactors reached their mass limit and thus turned into stationary conveying mode. The reaction is supposed to reach stationary mode after about 8.5 h. The product leaving reactor 4 (3.10 kg/h) was analyzed. The reaction yield conversion of 99% regarding the first base and a selectivity of 87% for preparation of ethyl cyanoacetate.

Example 7:

Example 6 was repeated at 15 °C. The reaction yield conversion of 97.5% regarding the first base and a selectivity of 91 .9% for preparation of ethyl cyanoacetate.

Example 8:

Chloroacetic acid (compound of formula III, wherein A is a bond and Hal is CI) was molten in a heated tank. During the trial the tank was refilled with molten acid.

A reactive distillation column with an inner diameter of 50 mm was used. The column was made of glass and the internals (Sulzer Katapak SP1 :1 filled with Amberlyst 36 and Sulzer BX) from alloy steel. The column without extraction zone was used. Column set up from top to bottom:

0.40 m Sulzer^® BX, a feed inlet for compound of formula III, 1 .20 m Sulzer^® Katapak SP1 :1 , a feed inlet for compound of formula IV, a 0.80 m Sulzer^® Katapak SP1 :1 , and a reboiler.

For reaction start up, the column was fed via the acid feed tube with hot water. The reboiler was started after a sufficient level of water was reached in the bottom. When the column reached a temperature of 100 °C over total height the acid feed was switched from water to chloroacetic acid and the ethanol flow was started as well. The column was operated with a feed stream of 4.57 kg/h chloroacetic acid

(compound of formula III, wherein Hal is chloro and A is a bond) and 2.86 kg/h ethanol (compound of formula IV, wherein R is ethyl) with azeotropic concentration. A reflux ratio of 0.9 and a heating duty of 2000 W have been used. After 5 h a stationary temperature profile was observed. Within further 4 h, samples from top and bottom showed that a stationary state was reached. Finally, a temperature of 134 °C was observed in the reboiler and 78.9 °C at the top. The conversion of chloroacetic acid was 33.1 %. The assay measured of the compound of formula II was 85wt%..

Example 9:

Example 8 was repeated with a feed of chloroacetic acid (compound of formula III, wherein A is a bond and Hal is CI) of 3.1 kg/h and a feed of ethanol (compound of formula IV with R is ethyl) of 3.14 kg/h. At a bottom temperature of 154 °C a conversion of 46.1 % was observed. The assay measured of the compound of formula II was 82wt%.

Claims

Claims:

1 . A cyanidation process for obtaining a compound of formula

N≡C-CH₂-A-C(O)-OR I,

wherein A denotes a bond or a divalent spacer selected from alkylene and arylene groups, and R is a Ci_-4 alkyl group, said process comprising:

reacting a compound of formula

Hal-CH₂-A-C(O)-OR II,

wherein Hal is a halogen atom selected from F, CI, Br and I, and wherein A and R are as defined above, with hydrogen cyanide in the presence of a first base, wherein the molar ratio between hydrogen cyanide and said first base is from 1 :0.3 to 1 :0.95 and the molar ratio between hydrogen cyanide to the compound of formula II is in the range from 1 :1 to 1 :4.

2. The process of claim 1 , wherein A is a bond or is selected from linear or

branched Ci_-5 alkylene and Ce-ιο arylene groups, preferably is a bond or a linear Ci_-5 alkylene group.

3. The process of claims 1 or 2, wherein at least 50% of the total amount of HCN used in the process and at least 10% of the total amount of the compound of formula II, wherein A, Hal and R are as defined above, used in the process are fed to the reaction zone as a premix comprising HCN and said compound of formula II.

4. The process of any of claims 1 to 3, wherein said premix comprises between 20 to 80% of the total amount of the compound of formula II, wherein A, Hal and R are as defined above, used in the process.

5. The process of any of claims 1 to 4, wherein the molar ratio of the first base to the compound of formula II, wherein A, Hal and R are as defined above, is in the range from 1 :1 to 1 :5, preferably from 1 :2 to 1 :4.

6. The process of any of claims 1 to 5, wherein the ratio of total molar amount of HCN fed to the reaction mixture and total molar amount of the first base fed to the reaction mixture is at least 10:9.

7. The process of any of claims 1 to 6, wherein the cyanidation is performed in the presence of a catalyst, said catalyst being obtained by mixing a second base, said second base having a pK_a of 8 or higher, and an acid, said acid having a pK_a of 5 or lower.

8. The process of any of claims 1 to 7, wherein the process is carried out in semi- batch or continuous mode.

9. The process of claim 8, wherein in semi-batch mode the molar ratio of the

catalyst to the first base is in the range of 0.01 :1 to 0.3:1 .

10. The process of claim 8 or 9, wherein in continuous mode, comprising at least one feed stream and at least one side stream.

1 1 . The process of claim 10, wherein the compound of formula II is provided in at least one feed stream.

12. The process of claims 10 or 1 1 , wherein in continuous mode the feed stream comprises the compound of formula II and optionally the catalyst, while the first base and the premix are independently fed to the reactor in at least one side stream.

13. The process of claim 12, wherein the molar ratio of the catalyst present in the at least one feed stream to the first base fed in the at least one side stream is in the range of 0.01 :1 to 0.3:1 .

14. The process of any of claims 1 to 13, wherein the process is carried out

without additional solvent.

15. A process for producing compound of formula

N≡C-CH₂-A-C(O)-OR I, wherein A is a single bond or a divalent spacer selected from alkylene and arylene groups, and R is a Ci_-4 alkyl group, according to the process of claims 1 to 14,

further comprising the process to obtain the compound of formula

Hal-CH₂-A-C(O)-OR II, wherein Hal is a halogen atom selected from F, CI, Br and I, wherein A denotes a bond or a divalent spacer selected from alkylene and arylene groups, and wherein R is a Ci_-4 alkyl group, by reacting a compound of formula

Hal-CH₂-A-C(O)-OH III, wherein Hal and A are as defined above,

with a compound of formula

ROH IV,

wherein R is as defined above, in a reactive distillation column comprising a reaction zone, a separation zone and, optionally, an extraction zone, wherein said process comprises:

(a) feeding said compound of formula IV into a reaction zone containing a heterogeneous catalyst and contacting said heterogeneous catalyst,

(b) feeding said compound of formula III above the reaction zone,

(c) removing said compound of formula II below the reaction zone of said reactive distillation column.

16. The process of claim 15, wherein A is a bond or the divalent spacer is

selected from the group consisting of linear or branched Ci_-5 alkylene and C6-io arylene groups, preferably is a linear Ci_-5 alkylene group.

The process of claims 15 or 16 wherein the compound of formula IV is a linear or branched Ci_-4 alkyl alcohol selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, sec-butanol, isobutanol and te/t-butanol.

18. The process of any of claims 15 to 17, wherein the compound of formula IV is fed into the reaction distillation column between the lower half to the end of the reaction zone.

The process of any of claims 15 to 18, wherein the compound of formula IV is fed into the reaction distillation column between the lower third to the end the reaction zone.

20. The process of any of claims 15 to 19, wherein the compound of formula II obtained in the first reaction process, optionally after further rectification, is directly fed in the second reaction process (cyanidation).