WO2003106463A1

WO2003106463A1 - Method for preparing magnesium dihalides and dialkyl magnesium derivatives

Info

Publication number: WO2003106463A1
Application number: PCT/FR2003/001683
Authority: WO
Inventors: Larissa Chtcheglova; Stéphane CARLOTTI; Alain Deffieux; Nicolas Poirier; Marianne Barbier
Original assignee: Mssa
Priority date: 2002-06-14
Filing date: 2003-06-05
Publication date: 2003-12-24
Also published as: FR2840901B1; AU2003255642A1; FR2840901A1

Abstract

The invention concerns a method for selective preparation of a magnesium dihalide activated in anhydrous hydrocarbon solvent medium by reacting metallic magnesium in divided form with an alkyl halide having one or more alkyl branches on the carbon atoms in α or β of the halogenated carbon. The invention enables the use of a solvent free of complexing additive. The invention also concerns a method for preparing a magnesium-dialkyl compound by reacting a lithium-alkyl compound and a magnesium dihalide prepared by the above method.

Description

Process for the preparation of magnesium dihalides and dialkyl-magnesium derivatives

Field of the invention

The present invention relates, on the one hand, to a process for the preparation in a hydrocarbon medium of activated magnesium dihalides and, from these compounds, to dialkyl-magnesium derivatives having secondary or tertiary alkyl groups and, on the other hand, the use of the corresponding derivatives as well as their solutions in hydrocarbons.

State of the art

Dialkyl magnesium compounds are widely used as intermediates in many chemical reactions. They are used, for example, in organic synthesis, as catalysts for the polymerization of olefins (see US Patent 6,187,883). They can also be used as starting materials for the synthesis of other organometallic derivatives. A method of synthesis of dialkyl-magnesians, very well known and published in the early sixties by Cowan and Mosher in Journal of Organic Chemistry, 27, 1 (1962), consists in reducing the alkyl mercurics with magnesium metal according to the reaction 1:

R ₂ Hg + Mg * - R ₂ Mg + Hg

(reaction 1)

However, the use of this method is very limited due to the high cost of alkyl mercurics and the toxicity problems associated with their handling. Another method is based on the elimination, in the presence of dioxane, of magnesium halide from an ethereal solution of Grignard reagents. The addition of dioxane to the medium leads to the formation of an insoluble complex between MgX ₂ and the dioxane which precipitates according to reaction 2 (cf. Schlenk, Berichte der Deutschen Chemischen Gesellschaft, 64, 734, 193 L). 2 RMgX (Et ₂ O) ^C4H8 ° ² R ₂ Mg + C ₄ H ₈ O ₂ . Insoluble MgX ₂

(reaction 2)

A major drawback of this method is the presence of ether (dioxane), part of which is complexed with the magnesium derivative. These oxygenated organic derivatives, even in very small quantities, are often undesirable for numerous applications such as, for example, in polymerization catalysis, where they can act as poison for active species (Ziegler-Natta) or modify the stereochemistry of reactions (dienes ).

A method for the synthesis of di - "- alkyl-magnesians, carrying linear alkyl chains of five or more carbon atoms, soluble in hydrocarbon solvents and free from all traces of ether, was developed by Glaze and Selman, J. Organometal. Chem., 5, 477, (1966), by direct reaction of magnesium metal with an alkyl halide according to reaction 3:

2 Mg + 2 RC1> - R ₂ Mg + MgCl ₂

(reaction 3)

However, the hydrocarbon solutions of these magnesium derivatives with linear alkyl groups have a very high viscosity, which makes them very difficult to handle, as well as obtaining products free of solid impurities. The presence of linear alkyl groups promotes very high states of association, which reduces the reactivity of these derivatives.

Solutions of magnesium derivatives carrying a secondary alkyl group according to formula 4, such as n, s-dibutyl-magnesium, on the contrary are clear and very fluid.

R- CH ₂ - CH ₂ - Mg- CH- CH ₂ - R

CH ₃ (formula 4) The synthesis of n, s-dibutyl-magnesium in hydrocarbons can be done in two stages in the absence of any complexing additive, as described in the US patent

3755478. The first is to react the magnesium metal with n-butyl chloride. A mixture of di-n-butyl magnesium and activated magnesium chloride is then formed. The next step consists in adding sec-butyl lithium to this mixture to form the mixed n-butyl, s-butyl-magnesium derivative according to the reaction.

5:

2 n-BuCl + 2 Mg _hydrocarbon > (n-Bu) ₂ Mg ₊ MgCl ₂ ^^> 2 n, s-Bu ₂ Mg + LiCl

(reaction 5)

Dialkyl-magnesians having two secondary or tertiary alkyl groups have certain advantages of solubility and reactivity with respect to derivatives having primary or primary and secondary alkyl groups. This is the case, for example, when these are used as co-initiators with an alkyllithium in anionic polymerization of styrene. Indeed, the formation of two polystyrene chains per atom of magnesium is observed, whereas only one increases when n, s-dibutyl-magnesium is used, and none in the case of n, n-dibutylmagnesium (see A. Deffieux et al., Macromol. Chem. Phys., 202, 3219, 2001). However, Kamienski and Eastham (see J. Organic Chem., 34, 1116, 1968) have shown that the di-sec-alkyl-magnesian derivatives could not be directly synthesized by reaction of magnesium metal with secondary alkyl halides in hydrocarbon solvents. It is the same with tertiary dialkylmagnesians. The reactions between the magnesium metal and the secondary or tertiary alkyl halides can take place only in the presence of organic bases such as ethers. Limited amounts of ethers are sufficient (10% based on the reactant) when activated magnesium powder is used. In contrast, stoichiometric ratios between ether and alkyl halide are required when magnesium shavings are used. These reactions however require a tedious operation to remove the ether present, in particular that complexed with the magnesium derivative. This step is delicate and does not guarantee a good result as to the total absence of ether. Several of these approaches concerning the preparation in the presence of ether of magnesium derivatives carrying branched alkyl groups (Rr; primary alkyl groups with branching, secondary or tertiary) are described in the literature, for example in US Pat. No. 3,766,280. In a first way, the first step consists in synthesizing the reagent of

Grignard by reaction of metallic magnesium with an alkyl halide in ether according to reaction 6 (a). An alkyl lithium is then added to the reagent of

Grignard in ether, which leads to a dialkyl-magnesium in solution and to more or less complete precipitation, depending on the nature of the halogen, of the lithium halide according to reaction 6 (b). It is also conceivable to prepare dialkyl-magnesians having branched alkyl groups from the reagents of

Grignard in ether without using alkyl lithium according to reaction 6 (a + c).

RrX + Mg _ether > RrMgX, ether (a)

RrMgX, ether + RrLi _ether > R ₂ Mg + LiX 0)

2 RrMgX, petroleum _hydrocarbon > R ₂ Mg + MgCl ₂ (c) codistillation where Rr represents a branched alkyl group (primary with branching, secondary, or tertiary).

(reaction 6)

The ether, part of which is complexed with dialkyl magnesium, must then be removed to be replaced by a hydrocarbon solvent. This can be achieved according to two different approaches: elimination by evaporation under vacuum at 80 ° C., leading to the drying of the dialkyl magnesium with the risk of its degradation, or co-distillation of the ether in the presence of hydrocarbon solvents introduced in several times.

These operations are long and tedious and do not guarantee the total absence of ether in the organometallic derivatives.

In a variant of this approach, when the reaction between a branched alkyl halide (Rr) and the magnesium metal is carried out in a hydrocarbon medium in the presence of only small amounts of ether, the dialkyl magnesium and the chloride of magnesium are formed at the expense of the Grignard reagent according to reaction 7 The problem of elimination of the ether still remains.

2 RX + ₂ Mg hydrocarbon _> ^ ₊ ^^

(reaction 7)

Kamienski et al, in US Pat. No. 3,766,280, have proposed another route for the synthesis of magnesium derivatives carrying branched alkyl groups in a hydrocarbon medium. The synthesis is carried out by reaction of an activated magnesium halide with branched alkyl lithiums according to reaction 8.

Mg ~ TX, ₂ + 2 RLi - hr-yd: rocarb —ure * »R ₂ Mg ° + 2 LiCl active

(reaction 8)

Commercial anhydrous magnesium chloride only allows very low yields of dialkyl magnesium (<20%) and requires very long reaction times. An activated form of the magnesium halide is necessary in order to improve the yield of the reaction. Several possibilities of activation of magnesium chloride are described: - stirring of a suspension of MgCl ₂ in isopropanol for several hours and elimination of the alcohol by co-distillation with toluene, stirring of a suspension of MgCl ₂ in ether for several hours and elimination of the ether by co-distillation with benzene. In both cases, oxygenated bases are present and must be removed carefully so as not to risk contaminating the synthetic products.

- Use of MgCl formed by reaction between magnesium powder and n-amyl chloride in benzene according to the procedure described by Glaze and Selman (see J. Organometal. Chem., 5, 477, 1966). The MgCl ₂ must be separated from the soluble di-amyl magnesium formed, then washed four times with pure benzene, before being reacted with in particular sec-butyl lithium or ter-butyl lithium. This method proves to be long and costly and limits the possibility of industrially developing the synthesis of secondary and tertiary dialkyl magnesium without the use of ether. Contrary to the teaching of this prior art, the object of the invention is to provide a simple and effective process for the preparation, in a purely hydrocarbon medium and in the absence of any additive or complexing solvent, of magnesium dihalides and , directly from these, dialkyl-magnesium derivatives having branched alkyl groups, in particular secondary or tertiary, that is to say whose carbon bound to magnesium is substituted respectively by two or three alkyl groups.

Subject of the invention

The subject of the invention is a process for the selective preparation of magnesium dihalide activated in anhydrous hydrocarbon solvent medium by reaction of metallic magnesium in divided form with an alkyl halide having one or more alkyl branches on the carbon atoms of α or β carbon halogen.

The dihalide is preferably a dichloride or a dibromide. Preferably, the alkyl halide is primary and has at least one alkyl branch on the carbon at α of that carrying the halogen. The reaction can be carried out batchwise in a reactor, or continuously in a tabular reactor. The solvents used are preferably linear or cyclic aliphatic hydrocarbon solvents and the aromatic hydrocarbon solvents, optionally as a mixture.

The invention also relates to a process for the preparation of a dialkyl-magnesium compound by reaction of an alkyl-lithian compound and a magnesium dihalide prepared by the above process. Preferably, the dialkyl magnesium compound has two secondary or tertiary alkyl groups. It can be prepared directly in situ by adding the alkyl lithian compound to the magnesium dihalide solution. It can also be prepared, either semi-continuously using two cascade reactors, one serving to prepare the magnesium dihalide and the other the dialkyl-magnesium compound, or continuously in a tubular reactor. Description of the invention

The process essentially consists in preparing, in anhydrous hydrocarbon solvent, a halide, in particular anhydrous magnesium chloride or bromide, by action on the powdered magnesium, in turn or in any other form, of a chloride or d 'a branched alkyl bromide X-Rr, the general formula of which is given in formula 9. The process can be stopped at this stage or continued so as to react directly on this hydrocarbon solution of magnesium halide in situ or in a separate step, a secondary or tertiary alkyl-lithiated derivative, of general formula 10.

X = halogen (Cl, Br, ...)

Rr = branched alkyl

Rα, R'α, Rβ, R'β, R = hydrogen or linear or branched alkyl group

(formula 9)

/ ^R '

Li C R,

\

R _j , R ₂ = linear or branched alkyl group R ₃ = hydrogen or linear or branched alkyl group

(formula 10)

(reaction 11)

In the process according to the invention, unlike the previous processes, in particular the process described in US Pat. No. 3,766,280 to Kamienski et al., The synthesis of the disec-alkyl-magnesium and diter-alkyl-magnesium derivatives can be carried out, if this is the case. desired, in a single operation in the same reactor from metallic magnesium and a branched alkyl halide X-Rr according to reaction 11 (a + c), then the addition of an alkyl lithian according to the reaction 12.

With the process according to the invention, it is possible to form in a hydrocarbon a magnesium dihalide according to the route a + c of reaction 11, in a highly active form, from metallic magnesium and an alkyl halide. branched X-Rr. This is made possible by an appropriate choice of the structure of the alkyl halide, and in particular by the presence of a branch on the alkyl group near the halogenated carbon, namely the carbon at α and / or β. Thanks to this connection, it is possible to direct the reaction, after transient passage through an organomagnesium (equation a, reaction 11), towards the preferential, even total, formation of magnesium dihalide, and of an inert hydrocarbon resulting from the coupling. of two alkyl groups (equation c, reaction 11). By a judicious choice of the structure of the alkyl halide and of the reaction conditions, one obtains after reaction a system containing almost exclusively the magnesium dihalide in hydrocarbons (solvent and coupling product). Only a few% of dialkyl magnesium derivatives, as well as possibly unreacted metallic magnesium, may be present.

This process of selective formation of magnesium dihalide results from a significant slowing down of reaction 11 (b). This can be attributed to the steric hindrance provided by the alkyl halide used. This has the effect of promoting reaction 11 (c). Thus, when the alkyl groups carrying the halogen atom are secondary, the reactivity of the corresponding halide with respect to metallic magnesium is practically suppressed. Conversely, when only one alkyl group is on the carbon at β, there is competition between routes (b) and (c) of reaction 11. It is therefore preferable to use alkyl halides, bromide. or chloride, the halogen of which is attached to a methylene carbon -CH ₂ -, and having at least one alkyl branch on the carbon at α of the halogen (groups R _α and / or R ' _α ) and / or two branches on β carbon (R _β and / or R ' _{β groups} ). The process is particularly advantageous because of the purity and the very high reactivity of the magnesium dihalides thus formed in a purely hydrocarbon medium. Furthermore, the magnesium dihalides prepared according to the invention can be directly used to carry out the synthesis of organomagnesium derivatives, in particular the secondary and / or tertiary di-alkyl derivatives of magnesium. For this, it suffices to carry out a simple addition to this reaction medium of secondary or tertiary alkyl lithium or their mixture in stoichiometric quantity according to reaction 12.

X = Cl, Br

Ri, R ₂ , = linear or branched alkyl group R ₃ = alkyl or hydrogen (reaction 12) One of the advantages of the process according to the invention is that it can operate in the same reactor by successively carrying out the in situ preparation of the magnesium dihalide, then that of the dialkyl magnesium. This synthesis process can also be adapted to the continuous synthesis of dialkyl-magnesians using a tubular type reactor.

One can however voluntarily differentiate the two phases of the operation or stop at the preparation of activated magnesium dihalide, which can be stored in solution and under inert atmosphere, or even possibly stored and transported, for various subsequent uses. Another advantage linked to the separate realization of the two phases of the synthesis of dialkyl-magnesians is the possibility of using a semi-continuous process, a first reactor used specifically for the preparation of magnesium dihalide, and a second connected to the first during the dialkylation phase by the alkyl lithians.

Examples

In the examples below, the yield of magnesium dihalide is calculated from the total halogen level in the solid fraction, isolated by filtration, washed with anhydrous solvent and dried under dynamic vacuum for several hours. The mass percentage of halogen is determined by turbidimetric determination after reaction of the sample with AgNO ₃ . The respective levels of formed dihalide and unreacted residual magnesium are then calculated using the following equations:% MgX ₂ = (% by mass X / molar mass X) x (molar mass MgX ₂ ) where X = Cl or Br

% Mg = 100 -% MgX ₂ .

The absence or concentration of Grignard type compounds (R2Mg / MgX2 or RMgX) possibly formed is checked by analysis and assay by atomic absorption of the magnesium content of the hydrocarbon liquid phase. The dialkyl-magnesium yield is determined by assay by atomic absorption of the magnesium content of the hydrocarbon solution after filtration and elimination of the solid phase. The amount of lithium chloride formed during the alkylation reaction and present in the solid fraction is determined by adsoption atomic. The possible presence of unreacted alkyl lithium is checked by atomic absorption assay of the lithium content of the hydrocarbon solution.

Example 1 (Synthesis of magnesium dichloride)

A mass of 19.4 g (0.8 mol) of magnesium powder (100 mesh) and a few iodine crystals are placed in a 1000 ml flask with a rounded bottom, fitted with 3 necks and equipped with a condenser. reflux. The flask is heated to vaporize the iodine, then cooled. The magnesium is suspended in 20 ml of hexane. A solution of 74 g (0.8 mol) of iso-butyl chloride in 350 ml of hexane is added slowly over an hour to the flask. The mixture is heated to reflux and stirred for 24 hours. After filtration and elimination of the liquid phase and volatile compounds, the yield of activated magnesium chloride is approximately 50% compared to the theoretical yield and 0.2 mol of magnesium chloride is obtained.

Example 2 (Synthesis of magnesium dibromide)

A mass of 0.243 g (0.01 mol) of magnesium powder (100 mesh) and a few iodine crystals are placed in a 100 ml flask with a rounded bottom, fitted with 2 necks and equipped with a reflux condenser. The flask is heated to vaporize the iodine, then cooled. A solution of 2.74 g (0.02 mol) of isobutyl bromide in 18 ml of cyclohexane is added to the flask over 10 min. The mixture is stirred with reflux for 8 h. The magnesium bromide yield is determined by assaying the bromine in the solid phase. It is close to 100% compared to the theoretical yield and all the iso-butyl bromide is consumed. Only a few traces of magnesium metal remain. After extraction with ether of a sample of the suspension of magnesium bromide the analysis by H NMR and by atomic absorption does not indicate any trace of formation of di-iso-butyl-magnesium. Example 3 (Direct synthesis of di-sec-butyl-magnesium)

A mass of 38.9 g (1.6 mol) of magnesium powder (100 mesh) and a few iodine crystals are placed in a 1000 ml flask with a rounded bottom, fitted with 3 necks and equipped with a condenser. reflux. The flask is heated to vaporize the iodine, then cooled. The magnesium is suspended in 20 ml of hexane. A solution of 148.1 g (1.6 mol) of iso-butyl chloride in 500 ml of hexane is added slowly for one hour to the flask. The mixture is heated to reflux and stirred for 24 hours. The yield of activated magnesium chloride is determined as previously on a sample of the solid phase. It is 50% compared to the theoretical yield and 0.4 mol of magnesium chloride is obtained. 308 ml of 1.3 N solution of sec-butyl lithium (0.7 mol) is added to the suspension of magnesium bromide. The mixture is stirred for 24 hours at 40 ° C. After filtration, 0.6 mol of lithium chloride is found in the solid phase by analysis of lithium by atomic adsorption. The liquid phase contains 0.3 mol of dialkyl-magnesium compound measured by atomic adsorption of magnesium. Analysis by 1H NMR of a sample of the liquid phase confirms that the dialkyl-magnesium formed corresponds for the most part (95%) to di-sec-butyl-magnesium, and the proportion of iso-butyl groups attached to magnesium instead sec-butyl groups is between 2 and 5%.

Example 4 (2-step synthesis of di-sec butyl-magnesium)

A mass of 0.486 g (0.02 mol) of magnesium powder (100 mesh) and a few iodine crystals are placed in a 1000 ml flask with a rounded bottom, fitted with 2 necks and equipped with a reflux condenser. The flask is heated to vaporize the iodine, then cooled. A solution of 1.85 g (0.02 mol) of isobutyl chloride in 18 ml of cyclohexane is added to the flask over 10 min. The mixture is heated to reflux and stirred for 9 hours. The yield of magnesium chloride is approximately 40% compared to the theoretical yield and 0.004 mol of magnesium chloride is obtained. The suspension is then transferred and stored under an inert atmosphere in a 1000 ml flask with a rounded bottom serving as a second reactor.

In a second step, 6.3 ml of 1.27 N solution of sec-butyl lithium (0.008 mol) in heptane is added in 10 min to the suspension of magnesium chloride (0.004 mole in 18 ml). The mixture is stirred for 1 hour at room temperature. After filtration to remove the solid phase, 22 ml of solution are obtained

0.18 N of di-sec-butyl-magnesium. Analysis by 1 H NMR of a sample of the solution confirms the selective formation of di-sec-butyl-magnesium without trace of isobutyl-magnesium groups.

Example 5 (Direct synthesis of di-sec-butyl-magnesium)

A mass of 0.486 g (0.02 mol) of magnesium powder (100 mesh) and a few iodine crystals are placed in a 100 ml flask with a rounded bottom, fitted with 2 necks and equipped with a reflux condenser. The flask is heated to vaporize the iodine, then cooled. A solution of 2.74 g (0.02 mol) of isobutyl bromide in 18 ml of cyclohexane is added to the flask for 10 min. The mixture is stirred with reflux for 7 h. The yield of magnesium bromide, determined by assaying bromine in the solid phase, is approximately 80% relative to the theoretical yield and 0.008 mol of magnesium bromide is obtained.

12.6 ml of 1.27 N solution of sec-butyl lithium (0.016 mol) is added to the suspension of magnesium bromide. The mixture is stirred for 1.5 hours at room temperature. After filtration, 28 ml of 0.3 N di-sec-butyl magnesium solution are obtained. The 1H NMR spectrum of a sample of the solution shows the presence of approximately 95% of sec-butyl groups associated with magnesium for 2 to 5% of isobutyl-magnesium groups.

Example 6 (prior art)

A mass of 0.486 g (0.02 mol) of magnesium powder (100 mesh) and a few iodine crystals are placed in a 100 ml flask with a rounded bottom, fitted with 2 necks and equipped with a reflux condenser. The flask is heated to vaporize the iodine, then cooled. A solution of 3.02 g (0.02 mol) of isoamyl bromide in 18 ml of cyclohexane is added to the flask for 10 min. The mixture is stirred with reflux for 4 h between 92 and 94 ° C. The yield of magnesium bromide is approximately 80% compared to the theoretical yield and 0.008 mol of magnesium bromide is obtained. 12.6 ml of 1.27 N solution of sec-butyl lithium (0.016 mol) is added to the suspension of magnesium bromide. The mixture is stirred for 1.5 hours at room temperature. After filtration, 29 ml of 0.43 N solution of dialkyl magnesium is obtained. The 1H NMR spectrum of a sample of the solution shows the joint formation of approximately 60% of di-sec-butyl-magnesium and 40% of di-iso-amyl-magnesium.

Example 7 (Synthesis of di-butyl magnesium)

A mass of 0.486 g (0.02 mol) of magnesium powder (100 mesh) and a few iodine crystals are placed in a 100 ml flask with a rounded bottom, fitted with 2 necks and equipped with a reflux condenser. The flask is heated to vaporize the iodine, then cooled. A solution of 2.74 g (0.02 mol) of isobutyl bromide in 18 ml of cyclohexane is added to the flask for 10 min. The mixture is stirred with reflux for 7 h. The yield of magnesium bromide is approximately 80% compared to the theoretical yield and 0.008 mol of magnesium bromide is obtained. 9.4 ml of 1.7 N solution of tert-butyl lithium (0.016 mol) is added to the suspension of magnesium bromide. The mixture is stirred for 1.5 hours at room temperature. After filtration, 27 ml of 0.34 N solution of di-tert-butyl magnesium is obtained. The 1H NMR spectrum of a sample of the solution confirms the formation of dialkyl-magnesium with very predominantly (> 95%) terbutyl groups bound to magnesium and approximately 2 to 5% of iso-butyl-magnesium groups.

Claims

claims

1) Process for the selective preparation of magnesium dihalide activated in anhydrous hydrocarbon solvent medium by reaction of metallic magnesium in divided form with an alkyl halide having one or more alkyl branches on the α or β carbons of the halogenated carbon.

2) The method of claim 1 wherein the magnesium dihalide is magnesium dichloride.

3) Process according to claim 1 and according to which the magnesium dihalide is magnesium dibromide.

4) Method according to one of claims 1 to 3, characterized in that the solvent medium does not contain any complexing additive

5) .Procédé according to one of claims 1 to 4, characterized in that the alkyl halide is primary and has at least one alkyl branch on the carbon in α of that carrying the halogen.

6) Method according to one of claims 1 to 5, characterized in that the magnesium dihalide is prepared in a batch reactor.

7) Method according to one of claims 1 to 5, and according to which the magnesium dihalide is prepared continuously in a tabular reactor.

8) Process for the preparation of a dialkyl-magnesium compound by reaction of an alkyl-lithian compound and a magnesium dihalide prepared by a process according to one of claims 1 to 7. 9) Method according to claim 8, characterized in that the dialkyl-magnesium compound has two secondary alkyl groups.

10) Method according to claim 8, characterized in that the dialkyl-magnesium compound has two tertiary alkyl groups.

11) A method according to claim 8, characterized in that the dialkyl-magnesium compound is prepared directly in situ by adding an alkyl-lithian compound in the solution of magnesium dihalide.

12) Method according to one of claims 8 to 10, characterized in that the dialkyl-magnesium compound is prepared semi-continuously using two reactors in cascade, one used to prepare the magnesium dihalide and the other the compound di-magnesian.

13) Method according to one of claims 8 to 11, characterized in that the dialkyl-magnesian compound is continuously prepared using a tubular reactor.