WO2002016304A1

WO2002016304A1 - Method for producing alpha fluoromalonic acid dialkyl esters

Info

Publication number: WO2002016304A1
Application number: PCT/EP2001/009320
Authority: WO
Inventors: Thorsten Müh; Paul Fiedler; Holger Weintritt; Winfried Westerkamp; Arndt Reinecke
Original assignee: Bayer Cropscience Ag
Priority date: 2000-08-24
Filing date: 2001-08-13
Publication date: 2002-02-28
Also published as: DE10041618A1; AU2001289799A1

Abstract

The invention relates to a novel, advantageous method for producing α fluoromalonic acid dialkyl esters of general formula (I) by reacting a compound of general formula (II) with an addition product of hydrogen fluoride and a trialkylamine, under pressure and at temperatures ranging from 103 °C to 130 °C. In formulae (I) and (2), R1 represents alkoxy having 1 to 6 carbon atoms, R2 represents hydrogen or fluorine, and R3 represents hydrogen, fluorine or chlorine.

Description

Process for the preparation of α-fluoro-malonic acid dialkyl esters

The invention relates to a new, advantageous process for the preparation of α-fluoro-malonic acid dialkyl esters.

α-Fluoro-malonic acid dialkyl esters are intermediates which can be used, for example, for the production of α-fluoro-acrylic acid esters (cf. EP-A-203 462). Starting from α-fluoro-acrylic acid esters, high-molecular, non-crystalline polymers are produced that are transparent and have softening temperatures above 10 ° C.

It has already become known that α-fluoro-β-keto ester can be obtained starting from ethyl bromofluoroacetate. For this purpose, ethyl bromofluoroacetate is reacted in a first reaction step with tri-n-butylphoshin to give the corresponding phosphonium salt, which is then converted into the corresponding ylene by reaction with n-butyllithium at -78 ° C. After acylation and saponification, α-fluoro-β-keto esters are obtained (cf. J. Org. Chem. 56, 273-277 (1991)). A major disadvantage of this process is the difficult accessibility of the starting products, the multi-stage process and the necessary complex procedure e.g. when handling phosphines and n-butyllithium, which require special safety measures and carry out the reaction at low temperatures. For this reason, this method cannot be used on an industrial scale.

Kim (cf. OY Kim, Synthetic Communications 2000, 30 (7), 1205-1212) describes the preparation of α-fluoro-β-keto esters starting from 2-fluoro-2-phosphonyl-1,3-dicarbonyl compounds by cleaving the phosphorus carbon bonds wet silica gel. However, this process is also unsuitable for industrial processes, since the starting compounds are expensive and because large amounts of silica gel have to be filtered off to isolate the products. In another process (cf. DE-A-42 37 882), α-fluoro-β-dicarbonyl compounds of the formula (B) are prepared starting from dicarbonyl compounds of the formula (A) by reaction with an adduct of hydrogen fluoride Trialkylamine at temperatures from 20 ° C to 100 ° C.

(A) (B)

The disadvantage of this process is the long reaction times, which are between 24 hours and 72 hours. Another disadvantage is that the product is only obtained in yields of 60% to 70%.

It has now been found that dialkyl a-fluoro-malonate of the general formula (I)

in which

R ^{1 represents} alkoxy having 1 to 6 carbon atoms and

R ^{2 represents} hydrogen or fluorine,

obtained if a dicarbonyl compound of the general formula (II) is obtained,

in which R ^{1 has} the meaning given above and

R ^{3 represents} hydrogen, fluorine or chlorine,

with an adduct of hydrogen fluoride with a trialkylamine at temperatures from 103 ° C to 130 ° C under pressure.

In the compounds of formula (II), R ^{1 is} in particular methoxy or ethoxy.

In the compounds of formula (II), R ¹ particularly preferably represents ethoxy.

In the compounds of formula (I), R is in particular hydrogen.

The radical definitions listed above or given in preferred ranges apply both to the starting compounds of the formula (II) and correspondingly to the end products of the formula (I).

It can be described as extremely surprising that in the process according to the invention, which is carried out under pressure, α-fluoro-malonic acid dialkyl esters are obtained in higher yields and higher purity than in the processes described in the prior art, which are carried out under normal pressure, since the Experts expect partial decomposition under pressure and consequently lower yields.

The method according to the invention has a number of advantages. Thus, α-fluoro-malonic acid dialkyl esters are obtained after half the reaction time, which is customary in known processes. In the process according to the invention, the reaction time is 12 hours, while in known processes it takes 24 to 72 hours to react (cf. DE-A 42 37 892). Another advantage is that the yields are at least 15% higher than conventional processes. The new process is therefore particularly well suited for large-scale use.

The dicarbonyl compounds of the general formula (II) and all other starting compounds are common commercial products or can be prepared from them by simple processes.

In order to carry out the process according to the invention, addition products of hydrogen fluoride onto trialkylamines are generally used which contain 1 to 3 moles of hydrogen fluoride per mole of trialkylamine, and this is preferably located

Ratio at 1: 1 to 2, particularly preferably at 1: 1.

Examples of suitable trialkylamines are those which contain the same or different alkyl groups each having 1 to 6 carbon atoms. Trialkylamines with three identical alkyl groups are preferred. Triethyl-a in is particularly preferred.

The addition products of hydrogen fluoride onto trialkylamine can be prepared in situ by metering triethylamine into liquid hydrogen fluoride. Alternatively, the addition products of hydrogen fluoride on trialkylamine can be obtained in situ by metering hydrogen fluoride into triethylamine.

The reaction temperatures can be varied within a substantial range when carrying out the process according to the invention. In general, temperatures from 103 ° C to 130 ° C, preferably at temperatures from 104 ° C to 110 ° C, particularly preferably at temperatures from 104 ° C to 107 ° C.

The process according to the invention is generally carried out under increased pressure (autogenous pressure). Generally one works at pressures of 1.3 to 9 bar, preferably at pressures of 1.3 to 4 bar. To carry out the process according to the invention for the preparation of the α-fluoromalonic acid dialkyl esters of the general formula (I), 1 to 4 moles of the adduct, preferably 1 per mole of the compounds of the formula (II), are generally employed per mole of the compounds of the formula (II) 3 moles a.

The procedure according to the invention is generally carried out as follows: The addition product of hydrogen fluoride onto trialkylamine is placed in a pressure-tight reaction vessel. The reaction vessel is closed pressure-tight and the reaction mixture heated to 103 ° C to 130 ° C. The dicarbonyl compounds of the general formula (II) are metered into this. The reaction mixture obtained is stirred after the addition. A pressure of 1.3 to 9 bar is established. It is then cooled, the reaction mixture is let down and water is added. The organic phase is separated off, washed with acid and optionally distilled.

The metering time of the dicarbonyl compounds of the general formula (II) is generally three to nine hours, in particular five to seven hours, particularly preferably 6 hours.

After the metering, the reaction mixture is generally stirred for a further three to nine hours, in particular five to seven hours, particularly preferably a further six hours.

The process according to the invention is used, for example, for the preparation of dimethyl α-fluoromalonic acid, which is used, for example, as an intermediate for

Production of α-fluoro-acrylic acid esters (cf. EP-A-203 462) can be used. Starting from α-fluoro-acrylic acid esters, high-molecular, non-crystalline polymers are produced that are transparent and have softening temperatures above 10 ° C. In addition, α-fluoro-malonic acid diethyl ester can be used for the preparation of fluorine-substituted heterocycles, for example are biologically active or of interest as intermediates for crop protection agents (cf. N. Ishikawa, J. Fluorine Chem. 1984, 25, 203, or EP-A 970057).

The following examples serve to explain the invention. However, the invention is not limited to the examples.

Preparation Examples

Example 1 Diethyl fluoromalonate

(Using 3 equivalents of triethylamine hydrofluoride per equivalent

Chlormalonester)

CH ₃ CH ₂ O— C— CH-COCH ₂ CH ₃

455 g (3.2 mol) of the addition product of 3.2 mol of triethylamine with 6.4 mol of hydrogen fluoride are placed in a pressure-resistant reaction vessel and a further 326 g (3.2 mol) of triethylamine are added. The reaction vessel is closed in a pressure-tight manner and the reaction mixture is heated to 105 ° C., 541 g of diethyl chloromalonate (purity 77%; 2.1 mol) are metered in at 105 ° C. using a pump within 6 hours. After the addition has ended, the reaction mixture is stirred at 105 ° C. for a further 6 hours. The mixture is then cooled to 40 ° C., the reaction vessel is depressurized and 750 g of water are added. The organic phase is washed with 150 g of 15% sulfuric acid. 423 g of a liquid are obtained which contains 73% (GC area) of diethyl fluoromalonate (yield: 81%).

Example 2 Diethyl fluoromalonate

(using 2 equivalents of triethylamine hydrofluoride per equivalent

Chlormalonester)

142 g of the addition product of 1 mol of triethylamine with 2 mol of hydrogen fluoride are placed in a pressure-resistant reaction vessel and a further 102 g (1 mol) of triethylamine are added. The reaction vessel is closed pressure-tight and the reaction mixture is heated to 105 ° C. Within 6 hours, 253 g

Diethyl chloromalonate (purity 77%; 1 mol) is metered in at 105 ° C. using a pump. After the addition has ended, the reaction mixture is stirred at 105 ° C. for a further 6 hours. It is then cooled to 40 ° C., the reaction vessel is depressurized and 600 g of water are added. The organic phase is washed with 100 g of 15% sulfuric acid. 223 g of a dark liquid, 74%

(GC-ISTD) contains fluoromalonate (yield: 92%).

Claims

claims

1. Process for the preparation of compounds of the general formula (I),

in which

R ^{1 represents} alkoxy having 1 to 6 carbon atoms and

R ^{2 represents} hydrogen or fluorine,

characterized in that a compound of the general formula (II),

in which

R ^{1 has} the meaning given above and

R ^{3 represents} hydrogen, fluorine or chlorine,

2. The method according to claim 1, characterized in that in the compounds of formulas (I) and (II) R ^{1 is} methoxy or ethoxy.

3. The method according to at least one of claims 1 to 2, characterized in that in the formulas (I) and (II) R and R each represent hydrogen.

4. The method according to at least one of claims 1 to 3, characterized in that the method is carried out at temperatures from 103 ° C to 110 ° C.

5. The method according to at least one of claims 1 to 4, characterized in that the method is carried out at 1.3 to 9 bar.

6. The method according to at least one of claims 1 to 5, characterized in that the adduct of hydrogen fluoride with a trialkylamine contains 1 to 3 moles of hydrogen fluoride per mole of trialkylamine.

7. The method according to at least one of claims 1 to 6, characterized in that the trialkylamine is triethylamine.

8. The method according to at least one of claims 1 to 7, characterized in that based on compounds of formula (II) 1 to 4 moles of

Addition product of hydrogen fluoride to trialkylamine.

9. The method according to at least one of claims 1 to 8, characterized in that the dicarbonyl compounds of the general formula (II) are metered into the adduct of hydrogen fluoride with a trialkylamine within three to nine hours.

10. The method according to at least one of claims 1 to 9, characterized in that the reaction mixture is stirred for 3 to 9 hours after metering.