HK1131786B - Grignard reactions in microreactors - Google Patents

Description

Grignard type reactions in microreactors

Technical Field

The invention relates to a process for Grignard type reactions, comprising mixing at least two fluids in a microreactor.

Background

Grignard type reactions are very important reactions in preparative chemistry. In general, the Grignard type reaction is a compound of formula (I) or (II)

R¹Mg-X (I)，

R¹-Mg-R¹ (II)

(wherein R is¹A halogen atom selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl and aralkyl groups, and wherein X is selected from chlorine, bromine and iodine), with a compound of formula (III)

R²-X (III)，

(wherein R is²Is alkyl, cycloalkyl, alkenyl, alkynyl, aryl and aralkyl, and X is halogen); or with compounds containing polar multiple bonds such as C ═ O, C ═ N, C ≡ N, C ═ S, N ═ O, and S ═ O. The compounds of formula I are known as Grignard reagents. Other uses of the compounds of formula I or II are in the exchange of halogen atoms of boron, silicon, tin or antimony compounds, or in the preparation of more reactive grignard compounds which are more difficult to obtain.

EP-A-1285924 discloses carrying out the Grignard reaction using ｃA single micromixer. The disclosed process is suitable for industrial scale production.

Continuous improvement and control of chemical reactions is a long-standing goal in the chemical industry. Better control of the reaction may result, for example, in improved safety, increased yield and/or purity of the reaction, or isolation of valuable highly reactive intermediate products. In particular, better control of reagent mixing, fluid flow rates, heat removal/extraction and catalytic efficiency is sought.

It would therefore be very helpful to be able to provide a general method for such improved control of the reaction. In particular, processes are sought that implement large scale exothermic reactions in a controlled manner.

Disclosure of Invention

The invention provides a method of performing a grignard reaction comprising mixing at least two fluids, one of the at least two fluids comprising a compound capable of reacting with a grignard reagent in a grignard type reaction (first reactant) and the other fluid comprising a grignard reagent (second reactant) and optionally further fluids, said mixing taking place in a microreactor (6) comprising at least one flow path (1) for one of the at least two fluids comprising the first or second reactant (a), said flow path comprising at least two reaction zones (2), each reaction zone comprising an injection point (3) for administering the other fluid (B) of the two fluids comprising the second or first reactant, the microreactor further comprising a mixing zone (4) and a reaction zone (5) in which the at least two fluids are in contact with each other, and wherein the microreactor optionally provides one or more additional residence time volumes, wherein in said method the one fluid of the at least two fluids comprising the first or second reactants forms a first flow, and wherein the other fluid of the at least two fluids comprising the second or first reactants is injected into said first flow along said flow path (1) from at least two injection points (3) in such a way that only a fraction of the amount needed to complete the grignard type reaction is injected at each injection point.

Usually a "microreactor" is used to describe a reactor in which the size of the reaction volume (perpendicular to the direction of flow) is about 10000 microns or less.

The expression "necessary to complete the reaction" means the amount that needs to be added, for example, to a single vessel in order to achieve "theoretical" completion of the reaction. In a simple 1: 1 reaction stoichiometry, equimolar amounts will be required. For the first reactant, BCl in the following reaction (xvi)₃One, two or three molar equivalents of grignard reagent with one-MgX group would be required to complete the reaction depending on the desired product. As in reaction (xviii) below, where the grignard reagent contains two-MgX groups, two molar equivalents of the first reactant are required to complete the reaction.

The most important use of magnesium in the preparation of organic chemistry is in the formation of grignard compounds from organic halides by reverse-polar reduction of carbon atoms with halogens. The carbon-magnesium base in magnesium organic compounds or grignard compounds is strongly polarized and the carbon atom attached to magnesium carries a negative charge. Grignard reagents suitable for the reaction in the process of the invention are compounds of formula (I) or (II)

R¹-Mg-X (I)，

R¹-Mg-R¹ (II)

Wherein R is¹A halogen atom selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl and aralkyl groups, and wherein X is selected from chlorine, bromine and iodine. In a preferred embodiment, compounds of formula I are used. The grignard compound can be stored under suitable conditions as follows. The compounds of formulae I and II are in Schlenk equibrium. Depending on the substituents, the equilibrium will shift to one side. Both compounds can be used equivalently, although the reaction of the compound of formula II is generally slower than that of the compound of formula I.

In a preferred embodiment, the grignard reagent may comprise two or more-MgX groups, which groups may be linked by linear, branched or carbocyclic groups. Accordingly, the compounds of formula I here and below may also be represented by compounds of formula (Ia) or (Ib), etc

XMg-Q-MgX (Ia)，

Wherein Q is selected from di-or trivalent hydrocarbon moieties such as cycloalkane, alkenyl, alkynylaryl and aralkyl groups as defined above, wherein one, two or more hydrogen atoms are substituted by a corresponding number of-MgX groups.

Each of the aforementioned radicals can optionally carry other functional groups that are not capable of reacting with the grignard compound under grignard type reaction conditions.

In particular compounds of the formula (III)

R²-X (III)，

(wherein R is²Selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl and aralkyl, and wherein X is halogen) and also polar multiple bond compounds containing one or more such as C ═ O, C ≡ N, C ≡ S, N ═ O and S ═ O or compounds having at least one activated hydrogen atom can be reacted in a grignard type reaction with grignard reagents and can be used with reference to the process of the invention.

The compounds containing the above polar multiple bonds may be selected from the group consisting of carbon dioxide, aldehydes, ketones, halogenated carboxylic acids, esters, imines, thioaldehydes, thioketones, and thioesters. Compounds having an activated hydrogen are, for example, carboxylic acids or compounds which carry one or more hydroxyl, amino, imino or thio groups.

The term "alkyl" here and below denotes a linear or branched alkyl group. By using "C_1-nBy the form-alkyl "is meant that the alkyl group has from 1 to n carbon atoms. C_1-6Alkyl represents, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl. The "alkyl" group R in formula I¹May carry one or moreAn additional-MgX group.

The term "cycloalkyl" here and below denotes a cycloaliphatic radical having 3 or more carbon atoms. Cycloalkyl denotes mono-and polycyclic ring systems, for example cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl or bornyl. Cycloalkyl radicals R in the formula I¹One or more additional-MgX groups may be present.

The term "alkenyl" here and below denotes a linear or branched radical bearing a C ═ C double bond, which is optionally substituted by one or more halogen atoms and/or optionally by C_1-6-alkyl radical, C_1-6-alkoxy or di-C_1-6-alkylamino group substitution. Examples are ethenyl, 1-propenyl, 1-butenyl or isopropenyl. Alkenyl radicals R in the formula I¹One or more additional-MgX groups may be present.

The term "alkynyl" here and hereinafter denotes a linear or branched radical with a C.ident.C triple bond, optionally substituted by one or more halogen atoms and/or optionally by C.ident.C triple bonds_1-6-alkyl radical, C_1-6-alkoxy or di-C_1-6-alkylamino group substitution. Examples are ethynyl, 1-propynyl, 1-butynyl, 1-pentynyl. Alkynyl radicals R in the formula I¹One or more additional-MgX groups may be present.

The term "aryl" here and below denotes an aromatic group, preferably phenyl or naphthyl, which is optionally further substituted by one or more halogen atoms and/or optionally by C_1-6-alkyl radical, C_1-6-alkoxy or di-C_1-6-alkylamino group substitution. Aryl radical R in formula I¹One or more additional-MgX groups may be present.

The term "aralkyl" here and hereinafter denotes a group selected from phenyl, naphthyl, furyl, thienyl, benzo [ b]Furyl, benzo [ b ]]C as defined above substituted by aryl or heteroaryl moieties of thienyl_1-8An alkyl group, said aryl or heteroaryl moiety being optionally substituted by one or more halogensAn element atom, an amino group and/or optionally C_1-6-alkyl radical, C_1-6-alkoxy or di-C_1-6-alkylamino group substitution. Aralkyl radical R in the formula I¹One or more additional-MgX groups may be present.

The term "alkoxy" here and below denotes a linear or branched alkoxy group. By using "C_1-nBy the form-alkoxy "is meant that the alkyl group has from 1 to n carbon atoms. C_1-6Alkoxy represents, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentoxy and hexoxy.

The term "cycloalkoxy" here and below denotes a cycloalkoxy group having 3 or more carbon atoms. Cycloalkyl represents, for example, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy or cyclodecyloxy.

The term "di-C" here and below_1-6-alkylamino "denotes a dialkylamino group comprising two alkyl moieties independently having 1 to 6 carbon atoms. di-C_1-6Alkylamino represents, for example, N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino, N-ethyl-N-hexylamino or N, N-dihexylamino.

The main reaction product of a Grignard type reaction is usually an intermediate with a group of, for example, -O-MgX or-S-MgX. The intermediate is converted to the target reaction product after solvolysis (e.g., hydrolysis).

Reactions (i) to (xviii) describe grignard reactions and reaction sequences carried out in a multiple injection microreactor according to the present method.

(i) By the formula I or II (wherein R¹And X is as defined above) with a compound of formula III

R²-X (III)，

(wherein R is²As defined above, and X is halogen, wherein the compounds of formula I and IIIWherein the halogens may be the same or different) to give a compound of the formula IV

R¹-R² (IV)，

(wherein R is¹And R²As defined above).

(ii) By the formula I or II (wherein R¹And X is as defined above) with a Grignard reagent

(a) Formaldehyde, or

(b) An aldehyde of the formula V

R²-CHO (V)，

(wherein R is²Selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl and aralkyl), or

(c) Ketones of the formula VI

R³-CO-R⁴ (VI)，

(wherein R is³And R⁴Which may be the same or different and are selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl and aralkyl),

primary, secondary and tertiary alcohols of formulae VII, VIII and IX, respectively, are obtained

(a)R¹-CH₂-OH (VII)，

(b)R¹-CHOH-R² (VIII)，

(c)R¹-CR³R⁴-OH (IX)，

(wherein R is¹，R²，R³And R⁴As defined above).

(iii) By the formula I or II (wherein R¹And X is as defined above) with carbon dioxide to produce a carboxylic acid of formula X

R¹-COOH (X)，

(wherein R is¹As defined above).

(iv) By the formula I or II (wherein R¹And X is as defined above) with an acetyl halide of the formula XI

R²-COX (XI)，

(wherein R is²As defined above, and wherein X is chlorine, bromine or iodine) to give a ketone of the formula XII

R¹-CO-R² (XII)，

(wherein R is¹And R²As defined above).

(v) By the formula I or II (wherein R¹And X is as defined above) with a formate of the formula XIII

HCOOR² (XIII)，

(wherein R is²As defined above) reaction, depending on the reaction conditions, can be carried out

(a) Formula R¹-aldehyde of CHO (wherein R¹As defined above) or

(b) A secondary alcohol of formula VIII

R¹-CHOH-R² VIII，。

(vi) By the formula I or II (wherein R¹And X is as defined above) with a carboxylic acid ester of the formula XIV

R²-COOR³ (XIV)，

(wherein R is²And R³As defined above) reaction, depending on the reaction conditions, can be carried out

(a) Ketones of the formula XII

R¹-CO-R² (XII)，

(wherein R is¹And R²As defined above) or

(b) Tertiary alcohols of formula XV

R¹-C(R²)₂-OH (XV)

(wherein R is¹And R²As defined above).

In a preferred embodiment, the process is useful for preparing triphenylmethanol from ethyl benzoate and phenyl magnesium bromide.

(vii) By the formula I or II (wherein R¹And X is as defined above) with a nitrile of the formula XVI

R²-CN (XVI)，

(wherein R is²As defined above) to give a compound of the formula XII

R¹-CO-R² (XII)，

(wherein R is¹And R²As defined above).

(viii) By the formula I or II (wherein R¹And X is as defined above) with an imine of the formula XVII

(R²)₂C＝NR³ (XVII)，

(wherein R is²And R³As defined above) to give a compound of the formula XII

R¹(R²)₂C-NHR³ (XII)，

(wherein R is¹，R²And R³As defined above).

(ix) By the formula I or II (wherein R¹And X is as defined above) with deuterium oxide to give a compound of formula XVIII

R¹-D (XVIII)，

(wherein R is¹As defined above).

(x) By the formula I or II (wherein R¹And X is as defined above) with sulfur to give a compound of formula XIX

R¹-SH (XIX)，

(wherein R is¹As defined above).

(xi) By the formula I or II (wherein R¹And X is as defined above) with ethylene oxide to give a compound of formula XX

R¹-CH₂)₂-OH (XX)，

(wherein R is¹As defined above).

(xii) By the formula I or II (wherein R¹And X is as defined above) with thionyl chloride to give a compound of formula XXI

(R¹)₂S＝O (XXI)，

(wherein R is¹As defined above).

(xiii) By the formula I or II (wherein R¹And X is as defined above) with a Grignard reagent

(a) A phosphoryl halide, or

(b) Phosphonic acid dihalides of the formula XXII

R²-POX₂ (XXII)，

(wherein R is²And X is as defined above), or

(c) Phosphinic acid halides of the formula XXIII

R²R³POX (XXIII)，

(wherein R is²And R³Identical or different and are as defined above, and wherein X is as defined above)

Reaction by halide substitution to give phosphine oxides of the formulae XXIV, XXV and XXVI, respectively

(a)(R¹)₃PO (XXIV)，

(b)(R¹)₂R²PO (XXV)，

(c)R¹R²R³PO (XXVI)，

(wherein R is¹，R²，R³And R⁴As defined above). The process is particularly important for the preparation of trioctylphosphine oxide.

(xiv) The mixed phosphine oxides can be obtained by a two-step process which first begins with a compound of formula I or II (wherein R is¹And X is as defined above) with a secondary phosphine of the formula XXVII

(R²O)₂PHO (XXVII)，

(wherein R is¹As defined above) to give a compound of formula XXVIII

(R¹)₂POMgX (XXVIII)，

(wherein R is¹And X is as defined above), followed by reacting a compound of formula XXVIII with a compound of formula III

R²-X (III)，

(wherein R is²And X is as defined above) to give a compound of the formula XXV

(R¹)₂R²PO (XXV)，

(wherein R is¹And R²As defined above).

In a preferred embodiment of the reaction sequence (xiv), the second step of the dosing of the compound of formula III can be carried out (a) outside the microreactor, (b) in another microreactor, or (c) in the same microreactor as the first reaction, after the formation of the compound of formula XXVIII at least one "adjacent" injection point.

(xv) By the formula I or II (wherein R¹And X is as defined above) with a compound of formula XXIX

R²-SiX₃ (XXIX)，

(wherein R is²And X is as defined above) to give compounds of the formulae XXX, XXXI and XXXII

R¹R²SiX₂ (XXX)，

(R¹)₂R²SiX (XXXI)，

(R¹)₃R²Si (XXXII)，

(wherein R is¹，R²And X is as defined above).

When the reaction proceeds to completion, the compound of formula XXXII will become the main product. The process is particularly applicable to aryl magnesium halides, preferably aryl magnesium bromides.

(xvi) By the formula I or II (wherein R¹And X is as defined above) with a Grignard reagent of formula MX_mWherein M is selected from the group consisting of the metals of 3 to 15 of the periodic Table and comprises boron, wherein X is as defined above and M is an integer of 3 to 5, which corresponds to the valency of the metal M, to give a compound of the formula XXXIII

X_m-nM(R¹)_n (XXXIII)，

(wherein M, R¹And m is as defined above, and wherein n corresponds to the number of halogen atoms X replaced), or alternativelyAfter hydrolysis, the compound of formula XXXIV is obtained

(HO)_m-nM(R¹)_n (XXXIV)

(wherein M, R¹And m and n are as defined above).

(xvii) By the formula I or II (wherein R¹And X is as defined above) with a compound of formula XXXV

R¹-C≡C-H (XXXV)，

(wherein R is¹As defined above) to give a further grignard reagent of formula XXXVI

R¹-C≡C-Mg-X (XXXVI)，

(wherein R is¹And X is as defined above).

(xviii) By reacting Grignard reagents of formula XXXVII

(wherein X is as defined above and A is- (CH)₂)_nA group and n is an integer equal to or greater than 3, or-CH₂-B-CH₂A group in which B is a carbocyclic ring having 5 to 7 ring carbon atoms) with a compound of the formula XXXVIII

L_mMX₂ (XXXVIII)，

(wherein L is selected from 1, 5-cyclooctadiene, carbon monoxide and aromatic hydrocarbons such as benzene, p-cymene or pentadienyl, and m is an integer equal to or greater than 1) to give compounds of formula XXXIX

(wherein M, L, A and M are as defined above).

In a preferred embodiment of reaction scheme xviii), in the compounds of formulae XXXVII and XXXIX, A is a carbocyclic ring analogous to

Wherein each ring may contain one or more further substituents, such as alkyl or alkoxy groups. Thus, in a further preferred embodiment of reaction scheme (xviii), (. eta.) may be⁵-C₅H₅)₂MCl₂And

the reaction gives a metallocycle compound of the formula

Wherein M is Ti, Zr, Hf, Nb.

Fig. 1 and 2 show two embodiments of injecting fluid B into fluid a at different injection points. The microreactor (6) in fig. 1 comprises one flow path with three injection points and the microreactor (6) in fig. 2 comprises two flow paths with three injection points, respectively. There may be more than two flow paths and there may be more than three injection points on each flow path. Thus, the second reactant can be injected at the injection point into the first stream of fluid generation comprising the first reactant. From an economic point of view, more expensive and/or more reactive reactants are preferably fed into the first stream comprising less expensive and/or less reactive reactants. In most cases the grignard reagent will be such a more expensive and/or reactive reagent.

Furthermore, there are no structural limitations to the injection point, mixing zone and/or reaction zone. The microreactors in fig. 1 and 2 are shown as linearly extending hollow for the purpose of enabling a better understanding of only a part of the reactor of the present invention. However, the flow path (1) may be curved as known in the art. Furthermore, the different mixing and/or reaction zones do not necessarily have to be of the same size in width and length. Furthermore, it is not necessary to use a microreactor comprising all the above features in one physical entity. It is also possible to connect additional injection points, mixing zones, reaction zones outside the flow path and optionally to cool or heat them.

When more than one injection point is used, only a fraction of the amount needed to complete the grignard reaction needs to be dosed, which results in an increase in the number of hot spots in the microreactor, while the temperature of each hot spot is reduced compared to a typical microreactor having only one mixing and reaction zone. Furthermore, as one of the two compounds is diluted in the first stream comprising the other compound, the formation of side products is reduced and the yield is improved. Thus, the process of the invention provides better control of the reaction.

Each of the at least two fluids may independently be a liquid, a gas, or a supercritical fluid in the present invention. Depending on the mixing properties of the mixing zone, the at least two fluids need not be completely miscible.

Suitable microreactors for the inventive method may comprise additional structural elements, such as temperature-adjustable retention volumes, temperature-adjustable premixing volumes and other elements known in the art, in addition to at least one general flow path, at least one injection point, at least one mixing zone and at least one reaction zone.

Microreactors have been found to be particularly useful for grignard type reactions with multiple injection points. Better control of the fluid grignard type reactions can be achieved according to the present invention, which can lead to significant improvements in yield and/or purity of the reaction products, as well as other advantages. The reaction starts with contacting the reaction fluids a and B in the mixing zone (3) and continues in the reaction zone (3). In a preferred embodiment, the flow path (1) has a width in the range of 10 to 10000 micrometers and has a cross-section of 0.1 square centimeters or less. More preferably, the width of the flow path is in the range of 10 to 500 microns, or more preferably in the range of 10 to 200 microns.

In a further preferred embodiment, the reservoirs of the reactants, the injection points (3), the mixing zone (4) and/or the reaction zone (5) or any other structural entity of the microreactor used are independently provided with heating or cooling. Preferably, the heating or cooling is provided by an external source. The heating or cooling may be provided to initiate, maintain and/or slow the reaction. Preferably, heating is provided to initiate and/or sustain the reaction, while cooling is provided to slow the reaction. In rare cases heating may be provided to slow down the reaction, cooling to initiate and/or sustain the reaction.

For fast reactions that occur substantially in the mixing zone, the reaction zone can be used to adjust the temperature of the reaction mixture before injecting the next component of the compound to react with the compound present in the first stream in a grignard type reaction.

In general, a first flow (1) of fluid containing the reaction product is terminated after exiting the microreactor. The fast exothermic reaction, which may be substantially complete as the reaction mixture passes through the mixing zone, may require additional cooling to inhibit the formation of by-products as it passes through the reaction zone. Performing a slow reaction to complete the conversion typically results in the formation of by-products. In a preferred embodiment, the product is isolated after termination of the reaction. For some grignard reactions the first stream flowing out of the reaction zone or microreactor can be put into an external holding volume for further reaction in case complete reaction cannot be achieved in the mixing zone, and for other grignard reactions the first stream flowing out of the reaction zone or microreactor can be terminated after the last injection point before it completes the reaction, thus avoiding excessive reaction.

It is known from the examples below that in the grignard reaction, the yield increases with the number of injection points. By comparing each additional injection zone with the efforts and drawbacks of connecting or constructing additional injection zones (new microreactor design, overall increase in required hardware, additional planning work, rising fluid pressures, increased risk of leakage), it was found that the method of the invention can be advantageously implemented in microreactors comprising not more than 7 reaction zones (injection points, mixing zones, reaction zones), preferably 3 to 6 reaction zones.

Glycol ethers, preferably bis (2-methoxyethyl) ether (diglyme) and 1, 2-dimethoxyethane (monoglyme, DME), are preferred solvents for carrying out the transient grignard reaction in the microreactor. In particular, at temperatures of 0 ℃ or lower, grignard reagents tend to flocculate, coagulate or even crystallize, thereby clogging the microstructure. It can be seen that the grignard reaction carried out in the microreactor in the presence of at least one glycol ether prevents (especially at low temperatures) flocculation, coagulation or even crystallization of the grignard and thus clogging of the microstructure (channels, micromixers, internal flow paths). It can be seen that (under the same conditions) the grignard solution comprising at least one glycol ether has a longer shelf life than the grignard solution without glycol ether. In addition, such grignard solutions can comprise about 20 wt-% or more of the grignard reagent when stored and/or fed into the microreactor at a temperature of about 0 ℃ or less, preferably about-5 ℃ or less, more preferably about-15 ℃ or less. In a further preferred embodiment, the grignard reagent is dissolved in a mixture comprising between 10 and 50wt. -%, more preferably between 20 and 40wt. -%, more preferably about 30wt. -% of at least one glycol ether. In another further preferred embodiment, the glycol ether is bis (2-methoxyethyl) ether and/or 1, 2-dimethoxyethane. Other suitable solvents that may be used in the process are anhydrous diethyl ether and/or tetrahydrofuran.

Other objects, advantages and features will be apparent from the claims and the description of the embodiments of the invention.

Drawings

Fig. 1 is a schematic diagram of a microreactor (6), the microreactor (6) comprising a flow path (1) through the whole microreactor and three reaction zones (2) embedded, each comprising an injection point (3), a mixing zone (4) and a reaction zone (5), wherein a fluid B is dosed into a fluid a.

Fig. 2 shows a schematic representation of a microreactor comprising two such flow paths.

Detailed Description

The microreactors used in the examples of the present invention and the comparative examples were made of different materials (glass or metal) and with different building systems. The part is an integral microreactor entity, wherein the injection point, the mixing zone and the reaction zone are built in one physical entity. The other type is formed by individual elements (injection point, mixing zone and reaction zone) connected by external fitting. Part of the microreactors can be temperature regulated by immersion in a temperature-controlled bath without any additional in-situ complex temperature regulation system. Other microreactors also incorporate an effective internal temperature regulation system wherein temperature control fluid is brought to the injection point, mixing zone and outer surface of the reaction zone to provide effective and rapid temperature regulation. To facilitate the evaluation of the effect on the number of injection points, the grignard reagent (second reactant) was dosed with the first reactant in a proportion corresponding to the number of entry points in all examples. About 50,33.3,25,20 or 16.6 mol-% of the second reactant is needed at each entry point, respectively, for two, three, four, five or six entry points, in order to achieve complete reaction. Typically the microreactor effluent (containing product) is quenched and collected. In most cases the effluent is quenched with HCl.

Example 1:

in two self-assembled multi-injection microreactors with 2 to 6 reaction zones, each reaction comprising one injection point, one mixing zone and one reaction zone, assembled from separate injection points, mixing zones and reaction zones, 2-chloropropionic chloride (13.5 wt%) in tetrahydrofuran (THF, 86.5 wt%) was reacted as fluid a and phenethyl magnesium bromide (1eq, 10 wt%) in THF (1eq, 90 wt%) was reacted as fluid B. The microreactor was placed in a bath at 20 ℃. The temperature regulation of the microreactor is dependent on the heat exchange at the outer surfaces of the individual components of the module. The microreactors of examples 1.1 to 1.5 comprise a reaction zone with an internal volume of about 0.2mL, which is hardly cooled between the injection points. The microreactors of examples 1.6 to 1.10, comprising a reaction zone with an internal volume of about 2.0mL, allow for Low Efficiency Cooling (LEC) between injection points. Flow rates of 20 and 40g/min were used. The second reactant is fed into the first reactant in an equimolar ratio. The yields of the product 4-chloro-1-phenyl-pentan-3-one collected after each reaction zone, corresponding to the feed rate and cooling conditions, are shown in tables 1 and 2.

Comparative example 1:

the reactants of the examples were reacted with and without cooling in a single injection microreactor equipped with an injection point, a mixing zone and a reaction zone. Flow rates of 20 and 40g/min were used. Fluid B (grignard reagent) is dosed to fluid a (first reactant) in such a way that the two reactants are present in an equimolar ratio in the mixing zone. The yields of 4-chloro-1-phenyl-pentan-3-one collected after each reaction zone and after termination of the reaction, corresponding to the feed rate and cooling conditions, are shown in table 1.

Example 2:

in two multi-injection microreactors with 4 reaction zones, each comprising one injection point, one mixing zone and one reaction zone with an internal reaction volume of 1.08mL, the two were reacted with 2-chloropropionic chloride (] 3.5% by weight) in tetrahydrofuran (THF, 86.5% by weight) as fluid a and phenethyl magnesium bromide (1eq, 10% by weight) in THF (1eq, 90% by weight) as fluid B. Microreactor MR1 incorporates internal heat exchange structure and provides efficient cooling (VEC), while temperature control of metal microreactor MR2 is achieved by immersing the microreactor in a temperature-regulating bath and provides only inefficient cooling (LEC) between injection points. The temperature is shown in table 3. Total flow rates of 20 and 40g/min were used after the last injection. The second reactant (fluid B) is fed to the first reactant in a proportion corresponding to the number of entry points. About 25 mol-% of fluid B needs to be fed to the first stream at each entry point, relative to two, three or four entry points, to achieve complete reaction. After the last injection, the reagents of fluid B and fluid a are dosed in equimolar amounts. The yields of 4-chloro-1-phenyl-pentan-3-one collected after each reaction zone and after termination of the reaction, corresponding to the feed rate and cooling conditions, are shown in table 3.

Example 3:

the reaction of example 1 was carried out in two different microreactors at a flow rate of 18 g/min. MR2 is a metal microreactor immersed in a cooling bath and without other cold zone facilities (LECs), and MR3 is a glass microreactor equipped with an active cooling system with internal heat exchange structure similar to MR1 to provide high efficiency cooling (VECs). The yields obtained with the two-injection microreactor at-20, 0 and 20 ℃ (examples 3.1 and 3.3), respectively, or with the three-injection microreactor at-20, 0 and 20 ℃ (examples 3.2 and 3.4), respectively, are collected in table 4.

Comparative example 2:

the yields obtained by carrying out the reaction of example 1 under the conditions of example 3 with a microreactor having one injection point are collected in table 4 (comparative examples 2.1 and 2.2).

Example 4:

in a commercial multi-injection microreactor from Corning, each reaction comprising one injection point, one mixing zone and one reaction zone, two were reacted with dimethyl oxalate (10, 15 or 20 wt%, respectively) contained in bis (2-methoxyethyl) ether (ad100 wt%) as fluid a and ethyl-magnesium chloride (19.1 wt%) contained in a mixture of bis (2-methoxyethyl) ether (30 wt%) and tetrahydrofuran (THF, ad100 wt%) as fluid B. HCl in HCl/Mg at a molar ratio of about 1.15 is used to terminate the reaction in the microreactor effluent. Table 5 shows the content of dimethyl oxalate in fluid a [ wt. -% ], the grignard/oxalate stoichiometric ratio [ mol/mol ], the total flow rate [ g/min ], the temperature of the heat reservoir for the thermal regulation of the microreactor, and the yield (Y, [% ]), conversion (C, [% ]) and selectivity (S, [% ]) of the product (2-MOB ═ methyl 2-oxo-butyrate), respectively.

Comparative example 3:

in a commercial single injection NIM microreactor from Corning, dimethyl oxalate (10, 15 or 20 wt%, respectively) contained in bis (2-methoxyethyl) ether (ad100 wt%) was used as fluid a and ethyl-magnesium chloride (19.1 wt%) contained in a mixture of bis (2-methoxyethyl) ether (30 wt%) and tetrahydrofuran (THF, ad100 wt%) was used as fluid B, and both were reacted. HCl in HCl/Mg at a molar ratio of about 1.15 is used to terminate the reaction in the microreactor effluent. Table 6 shows the content of dimethyl oxalate in fluid a [ wt. -% ], the grignard/oxalate stoichiometric ratio [ mol/mol ], the total flow rate [ g/min ], the temperature of the heat reservoir for the thermal regulation of the microreactor, and the yield (Y, [% ]), conversion (C, [% ]) and selectivity (S, [% ]) of the product (2-MOB ═ methyl 2-oxo-butyrate), respectively.

Table 1:

comparative examples 1, 1 injection points

Examples 1.1, 2 injection points

Examples 1.2, 3 injection points

Examples 1.3, 4 injection points

Examples 1.4, 5 injection points

Examples 1.5, 6 injection points

40g/min, no cooling

22.5％

27.0％

n.a.

30.0％

31.0％

33.0％

20g/min, no cooling

21.5％

26.7％

31.0％

32.7％

35.0％

36.0％

n.a. ═ no data; LEC is "low efficiency cooling"; VEC-efficient cooling "

Table 2:

comparative examples 1, 1 injection points

Examples 1.6, 2 injection points

Examples 1.7, 3 injection points

Examples 1.8, 4 injection points

Examples 1.9, 5 injection points

Examples 1.10, 6 injection points

40g/min， LEC

22.5％

29.5％

33.5％

n.a.

37.5％

37.5

20g/min， LEC

21.5％

29.0％

33.5％

36.3％

37.5％

38.5％

n.a. ═ no data; LEC is "low efficiency cooling"; VEC-efficient cooling "

Table 3:

	example 2.1, MR1, 0 ℃, VEC	Example 2.2, MR1, 20 ℃, VEC	Example 2.3, MR2, 20 ℃, LEC
				10g/min	n.a.	n.a.	n.a.
20g/min	n.a.	n.a.	36.3％
				38g/min	n.a.	n.a.	35.0％
40g/min	46.3％	40.7％	n.a.
				60g/min	43.5％	37.1％	n.a.
80g/min	42.3％	35.9％	n.a.
				100g/min	40.1％	33.7％	n.a.

n.a. ═ no data; LEC is "low efficiency cooling"; VEC-efficient cooling "

Table 4:

	-20℃	0℃	20℃
				comparative example 2.1, MR2, LEC	29.8％	25.6％	21.6％
Example 3.1, MR2, LEC	n.a.	32.5％	28.1％
				Example 3.2, MR2, LEC	n.a.	36.7％	30.0％
Comparative example 2.2, MR3, VEC	36.1％	30.6％	22.8％
				Example 3.3, MR3, VEC	n.a.	36.7％	30.0％
Example 3.4, MR3, VEC	n.a.	30.0％	32.9％

n.a. ═ no data; LEC is "low efficiency cooling"; VEC-efficient cooling "

Table 5:

example #	Charge-1 [ wt. -% ]%]	Stoichiometric ratio [ mol/mol]	Flow rate [ g/min ]]	T [℃]	Y [％]	C [％]	S [％]
								4.1	10.0	1.17	39.9	-5	84.6	98.9	85.6
4.2	10.0	1.17	40.0	-15	89.2	100.0	89.2
								4.3	15.0	1.15	39.9	-5	81.7	97.8	83.5
4.4	15.0	1.11	40.0	-15	87.4	98.4	88.9
								4.5	20.0	1.14	39.9	-5	78.0	98.2	79.4
4.6	20.0	1.16	40.0	5	84.7	99.0	85.5
								4.7	20.0	1.07	40.0	5	70.9	92.6	76.5
4.8	20.0	1.11	40.0	-5	77.6	95.6	81.2
								4.9	20.0	1.05	40.0	-15	82.7	95.0	87.1

Table 6:

comparative example #	Charge-1 [ wt. -% ]%]	Stoichiometric ratio [mol/mol]	Flow rate [ g/min ]]	T [℃]	Y [％]	C [％]	S [％]
								3.1	10.0	1.17	40.2	-15	81.6	96.1	84.9
3.2	10.0	1.16	40.1	-5	77.3	94.9	81.5
								3.3	10.0	1.17	40.0	5	73.4	94.4	77.7
3.4	15.0	1.17	39.9	-5	67.7	94.9	71.3
								3.5	15.0	1.17	40.0	-15	74.0	96.6	76.6
3.6	20.0	1.23	38.7	-5	53.3	90.9	58.6

Claims (21)

1. A method of performing a Grignard reaction comprising mixing at least two fluids, one of the at least two fluids comprising a compound capable of reacting with a Grignard reagent in a Grignard type reaction (first reactant) and the other fluid comprising a Grignard reagent (second reactant) and optionally further fluids, said mixing taking place in a microreactor (6) comprising at least one flow path (1) for one of the at least two fluids (A) comprising the first or second reactant, said flow path comprising at least two reaction zones (2), each reaction zone comprising an injection point (3) for dosing the other fluid (B) comprising the two fluids of the second or first reactant, the microreactor further comprising a mixing zone (4) and a reaction zone (5) in which the at least two fluids are in contact with each other, and wherein the microreactor optionally provides one or more additional residence time volumes, wherein in said method the one fluid of the at least two fluids comprising the first or second reactants forms a first flow, and wherein the other fluid of the at least two fluids comprising the second or first reactants is injected into said first flow along said flow path (1) from at least two injection points (3) in such a way that only a fraction of the amount needed to complete the grignard type reaction is injected at each injection point.

2. The method of claim 1, wherein the flow path (1) has a width in the range of 10 to 10000 microns and has a cross-section of 0.1 square centimeters or less.

3. The method of claim 2, wherein the flow path width is in the range of 10 to 500 microns.

4. The method of claim 3, wherein the flow path width is in the range of 10 to 200 microns.

5. The method according to any of claims 1 to 4, wherein the injection point (3), the mixing zone (4) and/or the reaction zone (5) are independently provided with heating or cooling.

6. The method of claim 5, wherein heating or cooling is provided to initiate, maintain and/or slow the reaction.

7. The method of claim 6, wherein heat is provided to initiate and/or maintain the reaction.

8. The method of claim 6, wherein cooling is provided to slow the reaction.

9. The method of any of claims 1 to 4, wherein the microreactor (6) comprises 3 to 6 reaction zones (2).

10. The process as claimed in any of claims 1 to 4, wherein in slow reactions the reaction is terminated after the last reaction zone before completion.

11. The process of any one of claims 1 to 4, wherein the Grignard reagent (second reactant) is a compound of formula (I) or (II)

R¹-Mg-X (I)，

R¹-Mg-R¹ (II)，

Wherein R is¹Selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl and aralkyl groups, and wherein X is selected from chlorine, bromine and iodine.

12. The method of any one of claims 1 to 4, wherein the first reactant is a compound of formula (III)

R²-X (III)，

Wherein R is²Selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl and aralkyl groups, and wherein X is selected from chlorine, bromine and iodine.

13. The method of any one of claims 1 to 4, wherein the first reactant is a compound comprising one or more polar multiple bonds.

14. The process of any one of claims 1 to 4, wherein the first reactant is C ═ O, C ≡ N, C ≡ S, N ═ O, and S ═ O.

15. The method of claim 13 or 14, wherein the first reactant is selected from the group consisting of carbon dioxide, aldehydes, ketones, halogenated carboxylic acids, esters, imines, thioaldehydes, thioketones, and thioesters.

16. The method of any one of claims 1 to 4, wherein the first reactant is a compound having at least one activated hydrogen atom.

17. The method of claim 16, wherein the first reactant is selected from carboxylic acids and compounds bearing one or more hydroxyl, amino, imino, or thio groups.

18. Method for carrying out a grignard reaction according to any of the claims 1 to 4 in a microreactor, wherein the reaction mixture comprises at least one glycol ether.

19. The method of claim 18, wherein 10 to 50 wt% of at least one glycol ether is present.

20. The method of claim 18, wherein the glycol ether is bis (2-methoxyethyl) ether and/or 1, 2-dimethoxyethane.

21. The method of claim 18, wherein the temperature of the grignard reagent charged into the microreactor is 0 ℃ or less.