WO2010121769A2

WO2010121769A2 - Process for the preparation of dialkyl 3-alkoxyglutarates

Info

Publication number: WO2010121769A2
Application number: PCT/EP2010/002380
Authority: WO
Inventors: Paul Hanselmann; Wolfgang Wenger; Daniel Zollinger; Cornelia Zur Täschler
Original assignee: Lonza Ltd
Priority date: 2009-04-24
Filing date: 2010-04-19
Publication date: 2010-10-28
Also published as: WO2010121769A3; WO2010121768A1

Abstract

The invention relates to an one-step, continuous process for preparing a dialkyl 3- alkoxyglutarate of formula RO(CO)CH₂C(OR)CH₂(CO)OR, wherein R is C_1-6alkyl, by reacting 2 equivalents of ketene with 1 equivalent of an ortho formate of formula (RO)₃CH, wherein R is as defined above, in the presence of an acidic catalyst.

Description

Process for the preparation of dialkyl 3-alkoxyglutarates

The present invention relates to an one-step, continuous process for preparing dialkyl 3-alkoxyglutarates of formula RO(CO)CH₂C(OR)CH₂(CO)OR, wherein R is C^ alkyl.

Dialkyl 3-alkoxyglutarates are important C-5 building blocks for various products, such as insecticides and pharmaceutical substances. A known synthetic route for dimethyl 3-methoxy- glutarate is a two-step synthesis. In a first step, 3-methoxyglutaric acid dichloride is prepared from dichloromethyl methyl ether by reaction with two equivalents of ketene in the presence of zinc isobutyrate as catalyst. Reaction with methanol forms dimethyl 3-methoxyglutarate in a following step (DE 1 200 279). Another way for the preparation of dimethyl 3-methoxyglutarate is the methylation of dimethyl 3-hydroxyglutarate with methyl iodide and silver oxide (Yamamoto et al, Agric. Biol. Chem. 1990, 54 (12), 3269-3274). Both methods require a metal compound which has to be removed from the product after reaction. In addition, both methods require a halogenated compound as starting material which is expensive and produces halogenated waste after reaction.

Other two-step syntheses for producing dialkyl 3-alkoxyglutarates are disclosed in DK 158462 and in F. Sorm et al, Chemicke Listy pro Vedu a Prumysl, 1953, 47, 413-417. Both approaches first produce and isolate the alkyl 3,3-dialkoxypropionate by reacting 1 equivalent of ketene and 1 equivalent of the orthoformate. In a separate next step, the alkyl 3,3-dialkoxypropionate

(1 equivalent) is then subjected to a further addition of 1 equivalent of ketene in order to obtain the desired dialkyl 3-alkoxyglutarate. These two-step syntheses are burdensome and result in a lower yield of the glutarate due to losses in the isolation process of the propionate intermediate.

Therefore, it was an object of the present invention to provide an improved process suitable for preparing dialkyl 3-alkoxyglutarates in a one-step synthesis that can be easily carried out with cheap reactants.

According to the invention, this object is achieved by the process as claimed in claim 1.

What is claimed is an one-step, continuous process for preparing a dialkyl 3-alkoxyglutarate of formula RO(CO)CH₂C(OR)CH₂(CO)OR, wherein R is Ci_e alkyl, by reacting 2 equivalents of ketene with 1 equivalent of an orthoformate of formula (RO)₃CH, wherein R is as defined above, in the presence of an acidic catalyst, wherein the ketene and the orthoformate are continuously added in a molar ratio of at least 2: 1.

Here and as follows, the term "Ci-^ alkyl" is to be understood to mean any linear or branched alkyl group containing 1 to 6 carbon atoms. Examples of Ci_₆ alkyl are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropyl), hexyl, isohexyl (4-methylpentyl) and the like.

The term "reacting" means that according to stoichiometry two molecules of ketene react with one molecule of the ortho formate for forming one molecule of the dialkyl 3-alkoxyglutarate. In practice, of course, ketene can be used in a molar ratio of more than 2 : 1 to ensure a quick and complete reaction. Advanteously, ketene is applied in a molar ratio between 2 : 1 and 4 : 1, preferably between 2 : 1 and 3 : 1 (related to ketene : orthoformate).

The ketene used may be essentially neat or may contain inert gases that are chemically inert with respect to the starting material, product as well as the catalyst, such as nitrogen, carbon monoxide and/or carbon dioxide, which are advantageously removed from the reaction vessel, for example, by means of a suitable pressure-relief vent in order to prevent excessive pressure buildup.

According to the invention, the process is performed in a continuous mode. The term

"continuous" means that both the starting materials including the catalyst and the reaction products are continuously added and removed, respectively. If a solid catalyst is used, an immobilization of the catalyst may be made such as storing the catalyst in a suitable device like a basket so that the catalyst is passed through by the starting materials. According to the invention, the ketene gas, the orthoformate and the acidic catalyst are continuously reacted with one another. This can be done in any suitable equipment for continuous operation. In the simplest equipment type, the reactants are added continuously into a reaction vessel like a flask, a tank or a reactor, advantageously under stirring and cooling. Advantageously, when starting the continuous process the reactants are added into a solvent, as ketene is gaseous and reacts more efficiently with the dialkyl 3-alkoxyglutarate when it is distributed in a solvent. The glutarate product as obtained when performing the process according to the invention, is typically a liquid, which does not react with the reactants and thus may serve as a solvent. Preferably, the continuous process according to the invention is carried out in the product which is formed when carrying out the process of the invention, namely in dialkyl 3-alkoxyglutarate of formula RO(CO)CH₂C(OR)CH₂(CO)OR, wherein R is C_MS alkyl. Suitably, as a precedent operation before starting the continuous process, the reactants are, for example, added both in a fedbatch-wise manner, in which the ketene is the reactant that is added over time, and in the molar ratio of the fedbatch-wise process, so that first the corresponding amount of the dialkyl 3- alkoxyglutarate is formed.

Also preferably, the solvent is a combination of the formed product with at least one further solvent. Each organic solvent which does not react with ketene or any other component of the reaction mixture can be used as solvent. Suitable solvents are, for example, aliphatic or aromatic hydrocarbons and ethers. Most preferably, the process according to the invention is carried out in neat dialkyl 3- alkoxyglutarate, in particular in dimethyl 3-methoxyglutarate or dipropyl 3-propoxyglutarate, as solvent, which means that the solvent dialkyl 3 -alkoxyglutarate is not combined with any further solvent. Due to technical aspects, the vessel or reactor is suitably filled up with the solvent or the solvent combination to a minimum level allowing for a sufficient mixing quality and cooling capacity before the continuous addition is started.

When simultaneously charging the reactants, a product stream is withdrawn from the reaction vessel in a volume which corresponds to the volume of the reactants charged, for subjecting to the following work-up procedure. This may be accomplished, for example, via a simple overflow pipe or by pumping off, while the pump may be controlled using a level detector.

In another suitable equipment type, the reaction time can be controlled by keeping the reaction mixture in a loop before removing it from the reaction vessel. Typically, a loop reactor can be employed. Depending on the feed rate, efficient cooling may be required due to the highly exothermic reaction. It can be achieved by known means, such as a cooling jacket covering a substantial part of the loop or by a heat exchanger of conventional construction forming part of the loop. Here, the term "loop reactor" does not denote a certain design, but only the principle of operation. In the most simple case, the loop reactor consists of a circularly closed tube (loop) equipped with a circulating pump. The loop has at least one outlet for withdrawing a product stream and at least two inlets for feeding the starting materials.

The acidic catalyst can be directly added into the reaction vessel, or it can be mixed beforehand with the orthoformate and/or a solvent. The number and the positions of the feed lines have to be chosen accordingly. Preferably, the orthoformate is first mixed with the acidic catalyst and, optionally, with the solvent, whereupon the catalyst dissolves or just forms a suspension. This is advantageously applied in case a loop reactor is used. The resulting mixture is then fed into the reaction vessel.

In principle, each organic solvent in which the orthoformate is sufficiently soluble and which does not react with ketene or any other component of the reaction mixture can be used as solvent. Suitable solvents are, for example, aliphatic or aromatic hydrocarbons, ethers and esters. Preferably, the solvent is the dialkyl 3-alkoxyglutarate which is the product of the process according to the invention. However, it is also possible to dispense with a solvent, provided the orthoformate is liquid. In a preferred embodiment, the orthoformate is directly added to the reaction vessel without prior dilution in a solvent.

The ketene gas can be fed into the reaction mixture by any suitable gas distribution system, for example, by using a gas-entry tube or a sparger, which is optionally provided with a porous frit or at least one nozzle. Preferably, the gaseous ketene and the liquid mixture comprising orthoformate, catalyst and, optionally, solvent is introduced using a gas-liquid ejector, wherein the liquid flow passes through a nozzle which generates a high velocity jet of fluid, thus aspirating and entraining the ketene. Advantageously, the liquid-gaseous jet impinges on a baffle or the wall of an adjacent mixing tube, resulting in rapid dissipation of kinetic energy. This creates an intensive mixing shock zone, where the high turbulence produces a fine dispersion of bubbles. The ability to generate and finally disperse very small ketene bubbles into the liquid mixture leads to a very fast transfer of ketene in the liquid. The thus obtained two-phase mixture is finally injected into the fluid phase in the reaction vessel, resulting in optimal efficacy in the subsequent chemical reaction. In addition, this way of gas distribution allows a consistent, pressure-free flowing of ketene into the gas-liquid ejector, which is particularly desired as ketene is prone to polymerization under pressure. Optionally, an anti- swirl device directs, aligns and stabilizes the pumped liquid flow, before the liquid flow passes through the nozzle. This way of feeding in the ketene gas by means of a gas-liquid ejector is typically applied when conducting the reaction in a loop reactor (jet reactor). For example, such a reactor is also known as BUSS Loop^® reactor.

For the continuous process according to the invention, the reaction components are fed into the reaction vessel in an essentially simultaneous and continuous manner. This means that there are no major interruptions or substantial fluctuations in the molar ratio of the reactants. When working without the use of a loop, accurate stirring can help to keep a constant mixture which is essentially free from variations in the concentration of the reactants. Especially, when applying the loop technique, the circulation in the loop ensures good or even ideal mixing. However, it is not necessary to enforce an ideal mixing.

In a preferred embodiment, the ortho formate is selected from the group consisting of trimethyl orthoformate, triethyl orthoformate, tripropyl orthoformate and tributyl orthoformate. More preferably, the orthoformate is trimethyl orthoformate, triethyl orthoformate or tripropyl orthoformate.

The reaction is advantageously carried out at a temperature between -40 ⁰C and 50 °C. Optionally, the reactants may be pre-cooled before feeding into the reactor, in particular when a loop reactor is used. Preferably, the reaction temperature is between -20 ⁰C and 30 ⁰C, more preferably between -10 °C and 20 ⁰C.

The reaction can be catalyzed by all suitable acidic catalysts. Suitable acidic catalysts are both "classic" Lewis acids and "classic" Brδnsted acids, and also acidic polysilicates. Advantageously, the "classic" Lewis acids used are zinc(II) chloride, iron(III) chloride, aluminum chloride, boron trifluoride and adducts of boron trifluoride with ethers, esters and similar compounds. A preferred adduct of boron trifluoride is the diethyl ether adduct. Preferred examples of "classic" Brδnsted acids are sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid. Another example of a suitable Brδnsted acid is phosphotungstic acid (PTA), optionally in its hydrate form, and favorably alumina-supported.

Acidic polysilicates have Lewis and/or Brδnsted acid properties and are therefore likewise suitable for the process according to the invention. The acidic polysilicates can also be employed in modified form or as mixtures. The formulae below are only given to illustrate the polysilicates but are not meant to be interpreted as a limitation. Suitable acidic polysilicates are, for example, amorphous polysilicates of the allophane type; chain polysilicates of the hormite type, such as polygorskite; two-layer polysilicates of the kaolin type, such as kaolinite (Al₂(OH)₄[Si₂O₅]), and halloysite (Al₂(OH)₄[Si₂O₅] x 2 H₂O); three-layer polysilicates of the smectite type, such as sauconite (Na_{0 3}Zn₃(Si₁Al)₄Oi_O(OH)₂ x 4 H₂O), sapomte ([Ca₅Na]_{0 3}(Mg,Fe")₃(Si,Al)₄θio(OH)₂ x 4 H₂O), montmoπllonite (Mo ₃(Al₅Mg)₂Si₄Oi₀(OH)₂ x n H₂O, wherein M in natural montmorillonite denotes one equivalent of one or more of the cations Na⁺, K⁺, Mg²⁺ and Ca²⁺), vermiculite ([Mg,Fe",Al]₃(Al,Si)₄ O₁₀(OH)₂ x 4 H₂O), nontromte (Na₀

x 4 H₂O), and hectorite (Na_{0 3}(Mg,Li)₃Si₄Oi₀[F,OH]₂), three-layer polysilicates of the illite type; polysilicates having vaπable layers of the chloπte type; and tectopolysilicates, such as zeolites, preferably of type Y in its H-form.

If required, the acidic polysilicates of the process according to the invention may be activated by treatment with acid and/or by treatment with a metal salt solution and/or by drying, and in the case of zeolites preferably by ion-exchange and/or by heating.

In a preferred embodiment, the catalysts used are acidic polysilicates of the smectite type and zeolites. A particularly preferred acidic polysilicate of the smectite type is montmoπllonite, especially the types available under the names "montmorillonite K 10" and "montmorillonite KSF/O", which are available, for example, from the company Sϋd-Chemie.

The acidic catalyst is advantageously employed in the process of the invention in an amount between 0.1% by weight and 20% by weight (based on orthoformate); preferably between 0.5% by weight and 15% by weight. However, the amount depends on the activity of the catalyst and the reaction temperature.

When carrying out the reaction, it has to be ensured that the water content is as low as possible, since both ketene and orthoformate may react with water in an unwanted manner.

Work-up is carried out by methods commonly known in the art and essentially depends on the physical properties of the formed dialkyl 3-alkoxyglutarate and the other components of the reaction mixture. If a solid acidic catalyst is used, this is advantageously removed by filtration and the filtrate is worked up, whereas, if a liquid acid catalyst is used, this is first neutralized in the reaction mixture. The neutralization may be carried out, for example, by adding basic alkali metal salts, such as sodium hydroxide and potassium carbonate, or by adding alkali metal alkoxides, such as sodium methoxide and potassium ethoxide, or by adding similar basic reagents, such as anhydrous ammonia or hexamethylenetetramine (urotropine). Any precipitate may then be removed by filtration, and the filtrate can subsequently be purified, if required. Advantageously, a solid acid catalyst is used which is filtered off in a first work-up step. The residue thus obtained is then either discarded or re-used in the reaction mixture as acidic catalyst, after its purification and optional re-activation if required.

After removal of the acidic catalyst, the filtrate is worked up in a known manner, preferably by distillation, to obtain neat dialkyl 3-alkoxyglutarate. Advantageously, the unreacted ortho formate, which usually has a lower boiling point than the desired product, is distilled off after filtration and is then recycled into the reaction mixture.

A further aspect of the present invention is the preparation of a dialkyl glutaconate of formula RO(CO)CH₂CH=CH(CO)OR, wherein R is d_₆ alkyl, from the dialkyl 3-alkoxyglutarate of formula RO(CO)CH₂C(OR)CH₂(CO)OR, wherein R is C_t_₆ alkyl, which has been prepared according to the invention.

Dialkyl glutaconates are likewise important C-5 building blocks and, for example, are starting materials in the preparation of sulfonium initiators which are used in cationic polymerizable compositions especially for application in dental technology. Other examples for the use of dialkyl glutaconates are as intermediates for the preparation of insecticides and pharmaceutical substances.

According to the invention, the dialkyl 3-alkoxyglutarate of formula RO(CO)CH₂C(OR)CH₂(CO)OR, wherein R is Q^ alkyl, which has been formed as described above, is converted in an additional step by heating in the presence of an acid catalyst and elimination of one molecule of the corresponding alcohol (ROH) into the corresponding dialkyl glutaconate of formula RO(CO)CH₂CH=CH(CO)OR, wherein R is Ci_₆ alkyl. Suitable acids are both liquid acids and solid acids, like acidic salts, acidic activated silica gel, acidic clay minerals, acidic activated carbon, acidic zeolites and cation exchange resins in their H-form. Optionally, the salts can be attached to carrier materials or can be modified.

Suitable acids are, for example, sulfuric acid, orthoboric acid, orthophosphoric acid, methane- sulfonic acid,/j-toluenesulfonic acid, sulfanilic acid, sodium bisulfate, phosphorus pentoxide, aluminum phosphate, zinc chloride, aluminum chloride and acidic zeolites. Particularly suitable are sulfuric acid, orthophosphoric acid, methanesulfonic acid, /»-toluenesulfonic acid, sulfanilic acid, sodium bisulfate, phosphorus pentoxide, aluminum phosphate and acidic zeolites, hi a preferred embodiment the acid is sulfuric acid or methanesulfonic acid.

Preferably, the amount of acid employed is between 0.05% by weight and 15% by weight (based on dialkyl 3-alkoxyglutarate), particularly preferably between 0.1% by weight and 10% by weight.

The solvent used may be any solvent which does not react with the reaction components, such as, for example, ligroin. However, the elimination can also be carried out without solvent. Preferably, the reaction is carried out in the absence of a solvent.

Preferably, the elimination is carried out at a temperature between 50 °C and 300 °C, more preferably between 80 ⁰C and 250 ⁰C, and the reaction time is advantageously between 1 hour and 15 hours, preferably between 1 hour and 10 hours. Optionally, the reaction may also be carried out under reduced pressure. Expediently, the formed alcohol (ROH) is directly distilled off during reaction to allow for complete conversion.

After the elimination step, the dialkyl glutaconate obtained can be purified in a known manner, for example by direct rectification, if required under reduced pressure, or by a neutralization- extraction-distillation scheme.

Examples The examples below illustrate embodiments of the invention. However, this is not meant to be construed as a limitation. Example 1: Preparation of dimethyl 3-methoxyglutarate (continuous process)

(a) Fedbatch-wise preparation of the reactor

Under nitrogen atmosphere, a 2 L double-jacket glass reactor (with impeller mixer, gas-entry tube, dropping funnel and overflow) was charged with 150.3 g (1.4 mol, 1 equivalent) trimethyl orthoformate (Fluka) and 18.1 g (0.13 mol, 0.09 equivalents) boron trifluoride diethyl etherate (Fluka). At 0⁰C and under stirring, gaseous ketene (ketene content about 70%, remainder inert gases, such as N₂, CO and CO₂) was introduced at a rate of approximately 42 g/h (related to neat ketene) up to an amount of 125 g of neat ketene (3.0 mol, 2.1 equivalents).

(b) Continuous process The continuous feed was then started by adding simultaneously, but separately 42 g/h (0.4 mol/h) trimethyl orthoformate, 5.1 g/h (0.04 mol/h) boron trifluoride diethyl etherate and about 42 g/h (1.0 mol/h) of neat ketene (calculated; ketene content is as described above), so that the molar ratio of trimethyl orthoformate, boron trifluoride diethyl etherate and ketene was 1 : 0.1 : 2.5. As a consequence of continuously adding the starting materials, the corresponding volume of the reaction mixture overflew also continuously from the double-jacket reactor into a collecting vessel. The continuous feed was done at an internal temperature of 5-25 °C by cooling. After three hours, in-process control by ¹H-NMR showed that the conversion into dimethyl 3-methoxyglutarate was complete and that it was equal to the conversion of the fedbatch reaction of step (a). Therefore, the continuous addition was stopped, and the reaction mixtures from both the reactor and the collecting vessel were combined. Then, the acidic catalyst was neutralized with hexamethylenetetramine (urotropine), and the formed solid was filtered off. 530 g of crude dimethyl 3-methoxyglutarate was obtained having a purity of about 80% (by ¹H-NMR), corresponding to a yield of about 85% (related to trimethyl orthoformate). Methyl 3,3-dimethoxypropionate, possibly formed by addition of trimethyl orthoformate and ketene in a 1 : 1 molar ratio, could not be detected by ¹H-NMR, showing that the reaction was complete.

A small sample was purified by distillation to obtain dimethyl 3-methoxyglutarate in 98.8% purity (by GC). bpio__{l l mbar} = 108-112.5 ⁰C, and

¹H-NMR (400 MHz, CDCl₃): δ = 4.06 (broad quint., IH, J = 6 Hz), 3.70 (s, 6H), 3.38 (s, 3H), 2.63 (dd, 2H, J = 15.6, 5.8 Hz), 2.57 (dd, 2H, J = 15.5, 6.6 Hz) ppm. Example 2: Preparation of dipropyl 3-propoxyglutarate (continuous process)

(a) Fedbatch-wise preparation of the reactor

Under nitrogen atmosphere, a 2 L glass double-jacket reactor (with impeller mixer, gas-entry tube, dropping funnel and overflow) was charged with 1 18.4 g (0.62 mol, 1 equivalent) tripropyl orthoformate (SAFC Supply Solutions) and 11.9 g (84 mmol, 0.13 equivalents) boron trifluoride diethyl etherate (Fluka). At 0°C and under stirring, ketene (ketene content about 70%, remainder inert gases, such as N₂, CO and CO₂) was added at a rate of approximately 34 g/h (related to neat ketene) up to an amount of 86 g of neat ketene (2.0 mol, 3.2 equivalents).

(b) Continuous process The continuous feed was then started by adding simultaneously, but separately 69 g/h

(0.4 mol/h) tripropyl orthoformate, 4.5 g/h (32 mmol/h) boron trifluoride diethyl etherate and about 34 g/h (0.8 mol/h) of neat ketene (calculated; ketene content is as described above), so that the molar ratio of tripropyl orthoformate, boron trifluoride diethyl etherate and ketene was 1 : 0.08 : 2. The continuous feed was done over a period of 3 hours and at an internal temperature of 5-11 ⁰C by cooling. An IR-probe, placed in the reactor, showed that the ketene was continuously reacting and that no significant amount of diketene was formed by self- reaction of ketene. As a consequence of continuously adding the starting materials, the corresponding volume of the reaction mixture overflew also continuously from the double- jacket reactor into a collecting vessel. After three hours, the continuous addition was stopped, and the reaction mixtures from both the reactor and the collecting vessel were combined. Then, the acidic catalyst was neutralized with hexamethylenetetramine (urotropine), and the formed solid was filtered off. The crude filtrate contained about 50% of dipropyl 3-propoxyglutarate (by ¹H-NMR).

A small sample was purified by distillation to obtain dipropyl 3-propoxyglutarate in >95% purity (by ¹H-NMR).

¹H-NMR (400 MHz, CDCl₃): δ = 4.15 (broad quint., IH, J = 6 Hz), 4.05 (t, 4H, J = 6 Hz), 3.45 (t, 2H, J = 6 Hz), 2.60 (dd, 2H, J = 15, 6 Hz), 2.55 (dd, 2H, J = 15, 6 Hz), 1.66 (sext., 4H, J = 6 Hz), 1.53 (sext., 2H, J = 6 Hz), 0.95 (t, 6H, J = 6 Hz), 0.88 (t, 3H, J = 6 Hz) ppm.

Example 3: Preparation of dimethyl glutaconate

Under an atmosphere of nitrogen, 1.2 mL (22.3 mmol, 0.05 equivalents) of sulfuric acid (Fluka) was added to 80 g (0.42 mol, 1.0 equivalent) dimethyl 3-methoxyglutarate, as obtained in Example 1 or 2, in a distillation apparatus with round-bottomed flask. The mixture was slowly heated to 165 ⁰C, and the methanol formed was directly distilled off. After 7 hours, heating was stopped and the residue in the flask was mixed with a saturated solution of sodium hydrogencarbonate. After removal of the organic phase, the aqueous phase was washed three times with 50 mL diethyl ether each. Then, the organic phases were combined, washed with 250 mL brine, and distilled under reduced pressure. The yield was 45.9 g (69%) of dimethyl glutaconate (bp_<0 i _kPa = 89 ⁰C) with a purity of >98% (by ¹H NMR). The product obtained was a mixture of the cis-isomer and of the trans-isomer.

¹H NMR (400 MHz, CDCl₃): δ = 6.93 (m, 1 H), 5.86 (d, 1 H, J = 15.6 Hz), 3.66 (s, 1 H), 3.63 (s, 1 H), 3.17 (m, 2 H) ppm. 1³C NMR (100 MHz, CDCl₃): δ = 170.3, 166.3, 140.0, 124.4, 52.3, 51.8, 37.3 ppm.

Example 4: Preparation of dimethyl glutaconate

The reaction was carried out analogously to Example 3 using 15 g (79 mmol, 1.0 equivalent) of dimethyl 3-methoxyglutarate, as obtained in Example 1 or 2, and 0.8 g (8.3 mmol, 0.1 equivalents) of methanesulfonic acid (Aldrich) by heating to a temperature of 175 ⁰C. The resulting crude product had a content of 79% (by GC) of dimethyl glutaconate.

Example 5: Preparation of dipropyl glutaconate

The reaction was carried out analogously to Example 3 using 0.73 g (2.66 mmol, 1.0 equivalent) of dipropyl 3-propoxyglutarate, as obtained in Example 2, and 44 mg

(0.46 mmol, 0.17 equivalents) of methanesulfonic acid (Aldrich) by heating to a temperature of

225⁰C under a reduced pressure of 200 mbar. The resulting crude product had a content of 61%

(by GC) of dipropyl glutaconate.

¹H NMR (400 MHz, CDCl₃): δ = 7.05 (dt, IH, J = 16, 8 Hz), 5.95 (broad d, IH, J = 16 Hz), 4.1 (m, 4H), 3.25 (broad d, IH, J = 8 Hz), 1.65 (m, 4H), 0.95 (m, 6H) ppm.

Claims

1. An one-step, continuous process for preparing a dialkyl 3-alkoxyglutarate of formula

RO(CO)CH₂C(OR)CH₂(CO)OR, wherein R is d_₆ alkyl, by reacting 2 equivalents of ketene with 1 equivalent of an ortho formate of formula

(RO)₃CH, wherein R is as defined above, in the presence of an acidic catalyst, wherein the ketene and the orthoformate are continuously added in a molar ratio of at least 2: 1.

2. The one-step, continuous process of claim 1 , wherein the process is carried out in the product of claim 1 , which is dialkyl 3-alkoxyglutarate of formula RO(CO)CH₂C(OR)CH₂(CO)OR, wherein R is Ci_₆ alkyl, as solvent, optionally in combination with at least one further solvent.

3. The one-step, continuous process of claim 2, wherein the process is carried out without any further solvent.

4. The one-step, continuous process of any of claims 1 to 3, wherein the orthoformate is selected from the group consisting of trimethyl orthoformate, tri ethyl orthoformate, tripropyl orthoformate and tributyl orthoformate.

5. The one-step, continuous process of any of claims 1 to 4, wherein the reaction is carried out at a temperature between -40 ⁰C and 50 ⁰C, preferably between -20 ⁰C and 30 ⁰C.

6. The one-step, continuous process of any of claims 1 to 5, wherein the acidic catalyst is a Lewis acid, a Brδnsted acid or an acidic polysilicate.

7. The one-step, continuous process of claim 6, wherein the Lewis acid is selected from the group consisting of zinc(II) chloride, iron(III) chloride, aluminum chloride, boron trifluoride and adducts of boron trifluoride with ethers or esters.

8. The one-step, continuous process of claim 6, wherein the Brδnsted acid is selected from the group consisting of sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid and phosphotungstic acid.

9. The one-step, continuous process of claim 6, wherein the acidic polysilicate is selected from the group consisting of acidic, amorphous polysilicates of the allophane type; acidic, chain polysilicates of the hormite type; acidic, two-layer polysilicates of the kaolin type; acidic, three-layer polysilicates of the smectite type; acidic, three-layer polysilicates of the illite type; acidic, variable-layer polysilicates of the chlorite type; and acidic tectopolysilicates.

10. The one-step, continuous process of claim 9, wherein the acidic, three-layer polysilicate of the smectite type is selected from the group consisting of sauconite, saponite, montmorillonite, vermiculite, nontronite and hectorite.

1 1. The one-step, continuous process of any of claims 1 to 10, wherein the acidic catalyst is employed in an amount between 0.1 % by weight and 20% by weight, based on orthoformate.

12. The one-step, continuous process of any of claims 1 to 1 1, wherein in an additional step the formed dialkyl 3-alkoxyglutarate is converted by heating and in the presence of an acid into the corresponding dialkyl glutaconate of formula

RO(CO)CH₂CH=CH(CO)OR, wherein R is as defined in claim 1.

13. The one-step, continuous process of claim 12, wherein the acid is selected from the group consisting of sulfuric acid, orthophosphoric acid, methanesulfonic acid, p- toluenesulfonic acid, sulfanilic acid, sodium bisulfate, phosphorus pentoxide, aluminum phosphate and acidic zeolites.

14. The one-step, continuous process of claim 12 or 13, wherein the acid is employed in an amount between 0.05% by weight and 15% by weight, based on dialkyl 3- methoxyglutarate.

15. Use of a dialkyl 3-alkoxyglutarate as obtained according to any of claims 1 to 1 1 as an intermediate for preparing the corresponding dialkyl glutaconate.