阅读说明：本技术 在流动反应器中制备二苯甲酰基(烷基)丙烯酸酯和取代的二苯甲酰基(烷基)丙烯酸酯的方法 (Process for preparing dibenzoyl (alkyl) acrylates and substituted dibenzoyl (alkyl) acrylates in a flow reactor ) 是由 鲁道夫·J·达姆斯 鲁迪·W·范坎彭豪特 于 2018-06-07 设计创作，主要内容包括：本发明提供了一种制备二苯甲酰基(烷基)丙烯酸酯的方法,该方法包括向微流动反应器的混合室中加入二苯甲酮醇、包含至少一个羟基部分的二苯甲酮醇或取代的二苯甲酮醇、一种或多种碱、极性液体、(烷基)丙烯酰卤或3-卤代烷基羧基卤、以及与极性液体不可混溶的有机液体；以及产生包含一种或多种二苯甲酰基(烷基)丙烯酸酯和该一种或多种碱的一种或多种盐的产物流；其中该产物流具有有机部分和极性部分,该产物流的有机部分包含二苯甲酰基(烷基)丙烯酸酯、未反应的二苯甲酮醇或取代的二苯甲酮醇和该产物流中的有机副产物；并且其中进一步地包括以下情况中的任一者：(a)该有机液体包括式(I)的化合物；或(b)该方法还包括将式(I)的化合物加入到产物流中；或(c)该有机液体包括式(I)的化合物,并且该方法还包括将式(I)的化合物加入到产物流(I)中,<Image he="207" wi="469" file="DDA0002305875640000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>其中R<Sub>1</Sub>为H或C<Sub>1</Sub>至C<Sub>4</Sub>烷基；并且R<Sub>2</Sub>为任选地插入有一个或多个O原子的C<Sub>1</Sub>至C<Sub>12</Sub>烷基。(The present invention provides a method of preparing a dibenzoyl (alkyl) acrylate, the method comprising adding to a mixing chamber of a microfluidic reactor a benzophenone alcohol, a benzophenone alcohol or substituted benzophenone alcohol comprising at least one hydroxyl moiety, one or more bases, a polar liquid, an (alkyl) acryloyl halide or 3-haloalkyl carboxyl halide, and an organic liquid immiscible with the polar liquid; and producing a product stream comprising one or more dibenzoyl (alkyl) acrylates and one or more salts of the one or more bases; wherein the product stream has an organic portion and a polar portion, ofThe organic moiety comprises dibenzoyl (alkyl) acrylate, unreacted benzophenone alcohol or substituted benzophenone alcohol, and organic by-products in the product stream; and wherein further comprising any of the following: (a) the organic liquid comprises a compound of formula (I); or (b) the process further comprises adding a compound of formula (I) to the product stream; or (c) the organic liquid comprises a compound of formula (I), and the process further comprises adding the compound of formula (I) to the product stream (I), wherein R is 1 Is H or C 1 To C 4 An alkyl group; and R is 2 Is C optionally interrupted by one or more O atoms 1 To C 12 An alkyl group.)

1. A method of preparing a dibenzoyl (alkyl) acrylate or a substituted dibenzoyl (alkyl) acrylate, the method comprising:

the following were added to the mixing chamber of the microfluidic reactor:

a benzophenone alcohol or a substituted benzophenone alcohol comprising at least one hydroxyl moiety,

one or more bases sufficient to at least partially deprotonate the benzophenone alcohol or substituted benzophenone alcohol,

a polar liquid, which is a liquid having a polarity,

(alkyl) acryloyl halide or 3-haloalkylcarboxy halide, and

an organic liquid immiscible with the polar liquid in an amount sufficient to dissolve the (alkyl) acryloyl halide or 3-haloalkyl carboxy halide, wherein

(ii) a molar flow ratio of all of said hydroxyl moieties to the sum of all of said one or more bases of 1 to at least 1.1; and

producing a product stream comprising one or more dibenzoyl (alkyl) acrylates or substituted dibenzoyl (alkyl) acrylates and one or more salts of the one or more bases; and is

Wherein

The polar liquid added to the mixing chamber is sufficient to dissolve the one or more salts; and is

The product stream has an organic portion and a polar portion, the organic portion of the product stream comprising the dibenzoyl (alkyl) acrylate or substituted dibenzoyl (alkyl) acrylate in an amount of at least 80 wt% based on the total weight of the dibenzoyl (alkyl) acrylate or substituted dibenzoyl (alkyl) acrylate, unreacted benzophenone alcohol or substituted benzophenone alcohol, and organic byproducts in the product stream; and wherein further comprising any of the following:

(a) the organic liquid comprises a compound of formula (I); or

(b) The method further comprises adding a compound of formula (I) to the product stream; or

(c) The organic liquid comprises a compound of formula (I), and the process further comprises adding a compound of formula (I) to the product stream

Wherein

R₁Is H or C1-C4 alkyl; and is

R₂Is a C1 to C12 alkyl group optionally interrupted with one or more O atoms.

2. The method of claim 1, wherein the organic liquid comprises a compound of formula (I).

3. The method of any preceding claim, wherein the polar liquid comprises water.

4. The process according to any one of the preceding claims, wherein the molar flow ratio of the benzophenone alcohol or substituted benzophenone alcohol to the (alkyl) acryloyl halide or 3-haloalkylcarboxy halide is 1 to at least 1.1.

5. A method according to any preceding claim, wherein the mixing chamber of the microfluidic reactor is not cooled by a cooling device.

6. The method of any one of the preceding claims, wherein

The mixing chamber of the microfluidic reactor comprises an outlet; and is

Wherein the method further comprises the step of removing the (alkyl) acrylate from the outlet simultaneously with the adding step.

7. The method of any one of the preceding claims, wherein the one or more bases comprise at least one of: triethylamine, dimethylamine, trimethylamine, methyldiethylamine, alkali metal hydroxides and alkaline earth metal hydroxides.

8. The process of any preceding claim wherein the (alkyl) acryloyl halide or 3-haloalkylcarboxy halide is 3-chloropropionyl chloride.

9. The process according to any one of claims 1 to 7, wherein the (alkyl) acryloyl halide or 3-haloalkylcarboxy halide is an (alkyl) acryloyl halide.

10. The method of any one of claims 1 to 7 or 9, wherein the (alkyl) acryloyl halide or 3-haloalkylcarboxy halide is acryloyl chloride or methacryloyl chloride.

11. The method of any one of the preceding claims, wherein the mixing chamber of the microfluidic reactor has an internal volume of no more than 1 mL.

12. The method of any preceding claim, further comprising the step of adding water to the product stream.

13. The method of any one of the preceding claims, wherein the polar portion of the product stream is continuously separated from the organic portion.

14. The method of any one of the preceding claims, wherein in the compound of formula (I), R₁Is H or methyl, and R₂Is C1-C12 alkyl or tetrahydrofuranyl.

15. The method of any preceding claim, wherein the compound of formula (I) is methyl methacrylate, butyl acrylate, tetrahydrofurfuryl acrylate, 2-ethylhexyl acrylate, and 2-methylheptyl acrylate.

Background

(alkyl) acrylates have a variety of uses, such as monomers or comonomers for making various polymers. The (alkyl) acrylates can be produced industrially, for example by esterification of alcohols with (alkyl) acrylic acid under azeotropic conditions, wherein water is removed from the reaction mixture during the reaction by distillation. This process is not useful for the manufacture of all (alkyl) acrylates, especially those which are unstable at higher temperatures.

(alkyl) acrylates can also be prepared by adding an alcohol to (alkyl) acryloyl chloride. This reaction can be difficult to carry out on an industrial scale, since it is necessary to strictly exclude water from the reaction in order to carry out in good yield. Moreover, the reaction is highly exothermic and therefore requires very slow addition of the alcohol to the (alk) acryloyl chloride and effective cooling. Even in the case of cooling, the reaction may cause a risk of explosion or fire when carried out on an industrial scale.

Detailed Description

Throughout this disclosure, singular forms such as "a," "an," and "the/the" are often used for convenience; it should be understood, however, that the singular is intended to include the plural unless the context clearly dictates otherwise.

Some of the terms used in this application have special meanings as defined herein. All other terms will be known to the skilled person and have the meaning that the person skilled in the art has given them at the time of the present application.

Two or more liquids or solvents are "miscible" if they are soluble in any ratio in each other at room temperature and atmospheric pressure. Thus, two miscible liquids or solvents will form a solution when mixed in any ratio.

Two or more liquids are "immiscible" if they are insoluble in all proportions in each other at room temperature and atmospheric pressure. Immiscible liquids or solvents may still have some solubility in each other. For example, diethyl ether may form up to about 10% by weight solution in water, but is still immiscible in water, as it does not form a solution in all proportions.

When used with reference to the characteristics of one or more variable elements, "independently" means that any of the variable elements present at each occurrence within the specified limits can have the same or different characteristics, regardless of the characteristics of any other present reference element. Thus, if there are two occurrences of element "E," and element E can be independently selected from property Y or property Z, then each of the two occurrences of E can be Y or Z in any combination (e.g., YY, YZ, ZY, or ZZ).

"alkyl" refers to an aliphatic hydrocarbon group. The alkyl group can have any number of carbon atoms; the number of carbon atoms is generally denoted by the symbol "Cn" in this disclosure, where "n" is an integer corresponding to the number of carbon atoms. Thus, C1 represents one carbon atom, C2 represents two carbon atoms, C3 represents three carbon atoms, and the like. Typical alkyl groups are C30 or less, such as C26 or less, C24 or less, C22 or less, C20 or less, C18 or less, C16 or less, C14 or less, C12 or less, C10 or less, C8 or less, C6 or less, C4 or less, or C2 or less. Some alkyl groups are C1. Typical alkyl groups are C2 or greater, C4 or greater, C6 or greater, C8 or greater, C10 or greater, C12 or greater, C14 or greater, C16 or greater, C18 or greater, C20 or greater, C22 or greater, C24 or greater, C26 or greater, or C28 or greater. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, sec-butyl, isobutyl, cyclohexyl, cyclopentyl, 2-ethylhexyl, isooctyl, n-octyl, dodecyl, hexadecyl, docosyl and the like.

"alcohol" refers to a compound having a hydroxyl group or a deprotonated hydroxyl group.

"halide" and other forms thereof, such as "halo", are used to refer to a chloride, bromide, or iodide group. The halide ion used herein is most commonly chloride.

"hydroxy" refers to an OH group.

"aryl" refers to a fully conjugated cyclic hydrocarbon mono-radical. Examples of aryl groups include phenyl, naphthyl, and the like.

"arylene" refers to a cyclic hydrocarbon diradical that is fully conjugated. Examples of arylene groups include phenylene, naphthylene, and the like. Each of the diradicals in the substituted aryl group can be located on the conjugate ring or on a substituent.

"substituted aryl" refers to an aryl diradical in which one or more of the hydrogen atoms are replaced with a substituent. Typical substituents include alkyl, alkenyl, oxyalkyl, hydroxy, and the like. Exemplary substituted aryl groups include toluoyl, xylyl, hydroxyaryl, alkylhydroxyaryl, and the like.

"carboxy" refers to a C (O) diradical.

"carboxyhalide" refers to a carbon-centered group O ═ C — X where X is a halide.

"Alkylcarboxyhalide" refers to a compound characterized by a chemical bond between an alkyl group of at least two carbon atoms and a carboxyhalide.

"3-haloalkyl carboxyhalide" refers to an alkylcarboxy halide with a halide group covalently bonded to the carbon atom at the 3-position (i.e., the carbon atom beta relative to the carbonyl group). The alkyl group is typically a C2 alkyl group, in which case the 3-haloalkylcarboxy halide is a 3-halopropanoyl halide, such as 3-chloropropanoyl halide or 3-chloropropanoyl chloride. The alkyl group in the 3-haloalkylcarboxy halide may be substituted or unsubstituted; however, when substituted, there is at least one hydrogen atom bonded to the carbon in the 2-position (i.e., the carbon atom in the alpha position relative to the carbonyl group). Typical substituents include alkyl, oxyalkyl, oxyalkyloxyalkyloxyalkyloxyalkyl, ether, aryl, heteroaryl, alkaryl, alkheteroaryl, oxyaryl, oxaaryl, aralkyl, heteroaralkyl, oxyarylalkyl, oxaaralkyl and the like. The alkyl group in the 3-haloalkyl carboxy halide may also be unsubstituted, as is more common.

"acryloyl halide" means acryloyl chloride, acryloyl bromide, or acryloyl iodide.

"(alkyl) acryloyl halide" means an acryloyl halide or an acryloyl halide with an alkyl group covalently bonded to the carbon atom at the 3-position (i.e., the carbon atom in the beta-position relative to the carbonyl group).

"Diphenyl" and "substituted diphenyl" refer to the mono group of benzophenone or substituted benzophenone, respectively. The dibenzoyl radical having the chemical structure C₆H₄C(O)C₆H₅. The radical may be centered on any carbon of the aromatic ring (but not on the carbonyl carbon), although it is most often located at the 4-position. Substituted dibenzoyl groups are typically substituted with alkyl or oxyalkyl groups, but may also be substituted with aryl, substituted aryl, oxyaryl, substituted oxyaryl, heteroaryl, oxaaryl, alkenyl, hydroxy, and the like. When the substituent is an alkyl group, it is most commonly methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, sec-butyl, isobutyl, cyclohexyl, cyclopentyl, 2-ethylhexyl, isooctyl, n-octyl, dodecyl, hexadecyl or docosyl. When the substituent is an oxyalkyl group, it is most usually oxymethyl, oxyethyl, oxypropyl, oxyisopropyl, oxyn-butyl, oxytert-butyl, oxysec-butyl, oxyiso-butylButyl, oxocyclohexyl, oxocyclopentyl, oxo2-ethylhexyl, oxoisooctyl, oxyn-octyl, oxododecyl, oxohexadecyl or oxodocosyl. When the substituent is aryl, it is most commonly phenyl or naphthyl. When the substituent is an oxyaryl group, it is most commonly an oxyphenyl or oxynaphthyl group. When the substituent is substituted aryl, it is most commonly toluoyl or xylyl. When the substituent is a substituted oxyaryl group, it is most commonly an oxytoluoyl group or an oxyxylyl group. When the substituent is heteroaryl, it is most commonly furyl or pyridyl. Hydroxy substituents are also possible. The substituent may be in any position, but is most typically in the 4' position, especially when the radical is centered at the 4 position.

"Benzophenonols" and "substituted benzophenonols" are each intended to have the formula HO-C₆H₄-C(O)-C₆H₅Or a substituted version thereof. The alcohol moiety may be centered on any aryl carbon, but is most typically on the 4 carbon. When the benzophenone alcohol is substituted, it is typically substituted with an alkyl or oxyalkyl group, but may also be substituted with an aryl, substituted aryl, oxyaryl, substituted oxyaryl, heteroaryl, oxaaryl, alkenyl, hydroxyl, and the like. When the substituent is alkyl, the most common is methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, sec-butyl, isobutyl, cyclohexyl, cyclopentyl, 2-ethylhexyl, isooctyl, n-octyl, dodecyl, hexadecyl or docosyl. When the substituent is an oxyalkyl group, the most common is oxymethyl, oxyethyl, oxypropyl, oxyisopropyl, oxyn-butyl, oxyt-butyl, oxysec-butyl, oxyisobutyl, oxycyclohexyl, oxocyclopentyl, oxy2-ethylhexyl, oxyisooctyl, oxyn-octyl, oxydodecyl, oxyhexadecyl or oxyeicosyl group. When the substituent is aryl, it is most commonly phenyl or naphthyl. When the substituent is an oxyaryl group, it is most commonly an oxyphenyl or oxynaphthyl group. When the substituent is substituted aryl, it is most commonly toluoyl or xylyl. When the substituent is a substituted oxyaryl group, it is most commonly an oxytoluoyl group or an oxyxylyl group. When the substituent is heteroaryl, it is most commonly furyl or pyridyl.Hydroxy substituents are also possible. The substituent may be in any position, but is most typically in the 4' position, especially when the radical is centered at the 4 position. Suitable benzophenone alcohols or substituted benzophenone alcohols include 4-hydroxybenzophenone, 4-hydroxyethylbenzophenone, 2-hydroxybenzophenone, 3-hydroxybenzophenone, 4-alcoholic 4' -hydroxybenzophenone, 5-bromo 2-hydroxybenzophenone, 5-chloro 2-hydroxybenzophenone and the like. Most commonly, the benzophenone alcohol is 4-hydroxybenzophenone.

"Diphenyl (alkyl) acrylates" are ester condensation products of benzophenone alcohols and (alkyl) acrylates.

"substituted dibenzoyl (alkyl) acrylates" are ester condensation products of substituted benzophenon alcohols and substituted (alkyl) acrylates.

"molar flow ratio" of two substances is the ratio of the flow rates of the two substances in moles of substance per unit time. One of ordinary skill in the art can calculate the molar flow rate ratio by dividing the concentration of each species (in molar concentration) by its flow rate and then determining the ratio of the two resulting values. For example, if substance "X" is present in a liquid at a concentration of 2mmol/mL and is flowing at a rate of 1mL/min and substance "Y" is present in a liquid at a concentration of 4mmol/mL and is flowing at a rate of 2mL/min, then the molar flow rate ratio of X to Y is 1 to 1 (i.e., ((2mmol/mL X)/(1mLX/min)): ((4mmol/mL Y)/(2mL Y/min)). when the molar flow rate ratio refers in part to an acid, base or alcohol, then the moles of base are considered to be the moles of acidic or basic equivalent₂Present in the liquid at a concentration of 2mmol/mL and flowing at a rate of 1mL/min and the alcohol is present in the liquid at a concentration of 4mmol/mL and flowing at a rate of 2mL/min, Ca (OH)₂The molar flow rate ratio to alcohol is 2 to 1 (i.e., (2mmol/mL Ca (OH))₂×2mol OH/mol Ca(OH)₂)/(1mL Ca(OH)₂(4mmol/mL Y)/(2mL Y/min)). The molar flow ratio is sometimes expressed as "N to at least M" where N and M are values. This symbolic representation value M may be a prescribed value or greater. Thus, if the molar flow rate ratio of X to Y is "1 to at least 1", the molar flow rate ratio may be 1 to 1 or moreAny value greater, such as 1 to 1, 1 to 1.5, 1 to 2, 1 to 10, and the like.

Dibenzoyl (alkyl) acrylates or substituted dibenzoyl (alkyl) acrylates can be prepared by chemical reactions taking place in the mixing chamber of a microfluidic reactor. A benzophenone alcohol or substituted benzophenone alcohol, one or more bases sufficient to at least partially deprotonate the benzene alcohol or substituted benzene alcohol, a polar liquid, an (alkyl) acryloyl halide or 3-haloalkyl carboxy halide, and an organic liquid immiscible with the polar liquid and present in an amount sufficient to dissolve the (alkyl) acryloyl halide or 3-haloalkyl carboxy halide can be added to the microreactor as a component of the reaction.

Any microfluidic reactor may be used. Typically, the microfluidic reactor will have at least a first addition port and a second addition port for adding liquid to the mixing chamber of the microfluidic reactor. In many cases, there may be more addition ports. In many cases, only two, three or four addition ports are used to add material to the mixing chamber. When an unused addition port is present, the unused addition port is typically plugged to prevent or mitigate the aspiration of any unwanted material from outside the mixing chamber and the loss of reactants or products from the mixing chamber. One or more of the addition ports may have a check valve to prevent backflow, but this is not necessary in most cases, as the pressure of the reactant stream through the addition port is typically sufficient to prevent backflow. The mixing chamber of a microfluidic reactor will also typically have at least one outlet for the product stream to exit.

Some microfluidic reactors will have a mixing chamber with an internal volume of no more than 10mL, such as no more than 5mL, no more than 0.9mL, no more than 0.8mL, no more than 0.75mL, no more than 0.6mL, no more than 0.5mL, no more than 0.4mL, no more than 0.3mL, no more than 0.25mL, no more than 0.1mL, or no more than 0.05 mL. Microfluidic reactors typically have a mixing geometry for promoting mixing of components added to the reaction chamber. In many cases, the mixing chamber may be designed to produce a flow plug of ingredients such that backmixing of the material in the microfluidic reactor with material subsequently added to the microfluidic reactor is mitigated. The mixing chamber may have any suitable geometry, such as T-shaped, star-shaped, circuitous tube-shaped, and the like. Suitable microfluidic reactors are commercially available, for example, under the trade names IDEX 91 (ACHROM (Belgium) in Belgium) and LABTRIX START 1805-L-2 (Chemtrix BV, UK in UK), the latter of which may be fitted with glass microchips such as those available under the trade name TPE 3223(Chemtrix BV) which may be used as mixing chambers. Other microfluidic reactors have been described in, for example, U.S. patents 6,228,434 and 6,192,596.

An impinging flow microreactor may be used. Such reactors are designed with an addition port that directs the mixing of the reactant streams in a volume of the impinging flow reactor to form a product stream. In this case, the volume of the impinging flow reactor in which the reactant streams are mixed is the mixing chamber. The pressure of the reactant stream passing through the inlet pushes the product stream through the mixing chamber and out the outlet.

Any benzophenone alcohol or substituted benzophenone alcohol can be used as long as it contains at least one hydroxyl group that is capable of reacting under the reaction conditions with an (alkyl) acryloyl chloride (such as acryloyl chloride or methacryloyl chloride) or with a 3-haloalkylcarboxy halide (such as a 3-halopropanoyl halide, 3-chloropropanoyl halide, or 3-chloropropanoyl chloride).

In most cases, benzophenone alcohols are used. The most common benzophenone alcohol is 4-hydroxybenzophenone. Typically only a single benzophenone alcohol or substituted benzophenone alcohol is used and no other alcohols are included that react under the reaction conditions to form esters. This is most common because the product is typically desired as a single dibenzoyl (alkyl) acrylate or substituted dibenzoyl (alkyl) acrylate. However, mixtures of more than one benzophenone alcohol may also be used. In this case, the product will be a mixture of (alkyl) acrylates, at least one of which is a phenyl group having different ester moieties. The molar ratio of the different products will generally be similar to the molar ratio of the alcohol added to the mixing chamber of the microfluidic reactor. For example, when the resulting mixture is polymerized together into a single copolymer, it may be useful to prepare more than one (alkyl) acrylate (at least one of which is a dibenzoyl (alkyl) acrylate or substituted dibenzoyl (alkyl) acrylate) simultaneously in the same microfluidic reactor. In this case, the product stream may leave the microfluidic reactor, typically through an outlet port, to form a product stream, which may be fed directly or after separation of water into another reactor, for example a reactor for polymerizing a product mixture.

The hydroxybenzophenone or substituted hydroxybenzophenone may be any suitable hydroxybenzophenone or substituted hydroxybenzophenone. Suitable hydroxybenzophenones or substituted hydroxybenzophenones are those which can be reacted under the reaction conditions with (alkyl) acryloyl chlorides, such as acryloyl chloride or methacryloyl chloride, or with 3-haloalkylcarboxy halides, such as 3-halopropanoyl halide, 3-chloropropanoyl halide or 3-chloropropanoyl chloride, to form (alkyl) acrylic esters. Examples include 4-hydroxybenzophenone, alkyl substituted 4-hydroxybenzophenone, aryl substituted 4-hydroxybenzophenone and the like. 4-hydroxybenzophenones are the most commonly employed.

The one or more bases can be any base sufficient to at least partially deprotonate the benzophenone alcohol. Typically, the one or more bases comprise an amine base. Common amine bases include triethylamine, dimethylethylamine, trimethylamine, methyldiethylamine, and the like. Triethylamine is the most commonly used amine base. Alkali metal hydroxides such as sodium hydroxide or potassium hydroxide may also be used alone or in combination with amine bases such as triethylamine. Alkaline earth metal hydroxides, such as calcium hydroxide, may also be used, although this is not the case.

The polar liquid is typically water, most typically deionized water. Occasionally, other solvents are used. When the solvent is not water, it is generally not an alcohol or any other solvent that reacts with one of the reactants, as such a solvent may participate in the reaction. In some cases, alcohols may be used as the polar liquid and as the reactant, especially when two alcohols are used, one of which is a benzene alcohol and the other of which is a liquid alcohol. In such cases, the liquid alcohol is typically mixed with water.

In most cases, the polar liquid will dissolve all or part of the one or more bases. Most often, the polar liquid will dissolve all of the one or more bases. This is especially true when the base or bases are not liquid at the reaction temperature (which is typically room temperature). Thus, in most cases, the base or bases are added to the mixing chamber of the microfluidic reactor as a solution in a polar liquid (which is most typically water). The most commonly used bases, alkali metal hydroxides and triethanolamine are highly water soluble and can therefore be added to the mixing chamber of a microfluidic reactor in this manner. When the base is also dissolved in the organic liquid, the base may be added to the mixture chamber of the microfluidic reactor as a solution in the organic liquid. When the base is liquid at the reaction temperature (which is usually room temperature), the base may also be added neat to the mixture chamber of the microfluidic reactor, although this is not typical.

The benzophenone alcohol or substituted benzophenone alcohol plus any other alcohol that may be present reacts with at least one of the (alkyl) acryloyl halide or 3-haloalkyl carboxyl halide within the mixing chamber of the microfluidic reactor. In some cases, both (alkyl) acryloyl halide and 3-haloalkyl carboxy halide may be used, but this is not common.

When an (alkyl) acryloyl halide is used, it is typically an acryloyl halide. When an alkyl group is present, the alkyl group can be any alkyl group. Most commonly, the alkyl group is C10 or less, such as C9 or less, C8 or less, C7 or less, C6 or less, C5 or less, C4 or less, C3 or less, C2 or less, or C1. The alkyl group is most typically methyl. Thus, the most common (alkyl) acryloyl halides are acryloyl halides and methacryloyl halides, specifically acryloyl chloride and methacryloyl chloride.

When a 3-haloalkyl carboxy halide is used, the alkyl group can be any suitable alkyl group. Most commonly, the alkyl group is C10 or less, such as C9 or less, C8 or less, C7 or less, C6 or less, C5 or less, C4 or less, C3 or less, or C2. In many cases, the 3-haloalkyl carboxy halide is a 3-halopropanoyl halide, such as 3-halopropanoyl chloride, 3-chloropropanoyl halide, or 3-chloropropanoyl chloride. 3-chloropropionyl chloride is the most common.

The organic liquid is generally suitable for dissolving most, if not all, (alkyl) acryloyl halide or 3-haloalkyl carboxy halide and most, if not all, of the reaction product. In addition, in order to promote the reaction with the (alkyl) acryloyl halide or 3-haloalkylcarboxy halide, the benzene alcohol generally has a certain solubility in the organic liquid. The organic liquid is also suitable for dissolving all or some of the at least one base, but this is not essential.

The organic liquid is conveniently immiscible with the polar liquid. This immiscibility aids in separating the phenyl or substituted phenyl (alkyl) acrylate product, which is typically predominantly present in the organic liquid, from salts and other polar liquid soluble by-products. Since the polar liquid is typically water, the organic liquid is typically immiscible with water. Exemplary organic liquids include methylene chloride, ethyl acetate, butyl acetate, methyl ethyl ketone, methyl butyl ketone, and the like. Water-immiscible (alkyl) acrylates may also be used.

In practice, the materials described herein are added to the mixing chamber of a microfluidic reactor. The addition is typically through at least two addition ports. Thus, the benzophenone alcohol or substituted benzophenone alcohol is typically added through a first addition port and the (alkyl) acryloyl halide or 3-haloalkylcarboxy halide is typically added through a second addition port. The addition of benzophenone alcohol or substituted benzophenone alcohol through a port different from the port of the (alkyl) acryloyl halide or 3-haloalkyl carboxy halide prevents the chemical reaction of these reactants outside the mixing chamber.

Most commonly, two addition ports are used. In this case, a polar liquid such as water, one or more bases (such as triethylamine, alkali metal hydroxide, or both), and an alcohol are typically added through the first port. Most commonly the mixture is added as a solution in which the base or bases and the alcohol are dissolved in a polar liquid. The (alkyl) acryloyl halide or 3-haloalkyl carboxyl halide and the organic liquid are typically added through a second addition port. Typically, the (alkyl) acryloyl halide or 3-haloalkylcarboxy halide is added as a solution in the organic liquid.

Three or four addition ports may also be used. When three addition ports are used, the benzophenone alcohol or substituted benzophenone alcohol, the base or bases and the polar liquid can be added through a first addition port, typically as a solution, (alkyl) acryloyl halide or 3-haloalkylcarboxy halide can be added through a second addition port and the organic liquid can be added through a third addition port. Alternatively, the benzophenone alcohol or substituted benzophenone alcohol can be added through a first addition port, the polar liquid can be added through a second addition port, and the (alkyl) acryloyl halide or 3-haloalkylcarboxy halide can be added through a third addition port, typically as a solution. When four addition ports are used, the benzophenone alcohol or substituted benzophenone alcohol and the one or more bases can be added through a first addition port, the (alkyl) acryloyl halide or 3-haloalkyl carboxyl halide can be added through a second addition port, the polar liquid can be added through a third addition port, and the organic liquid can be added through a fourth addition port.

Other variations are possible when three or more addition ports are used. In one such variation, the benzophenone alcohol or substituted benzophenone alcohol can be added to the organic liquid rather than the polar liquid. In one example of this variation, the benzophenone alcohol or substituted benzophenone alcohol can be added as a solution in the first organic liquid through a first addition port, the (alkyl) acryloyl halide or 3-haloalkylcarboxy halide can be added as a solution in the second organic liquid through a second addition port, and the base or bases can be added as a solution in the polar liquid (typically water) through a third addition port. The first organic liquid or the second organic liquid may be the same or different, and may be selected from any of the organic liquids discussed herein. Other variations are also possible, most of which would keep the (alkyl) acryloyl halide or 3-haloalkyl carboxy halide separate from the organic liquid outside the mixing chamber to avoid unwanted chemical reactions.

The components may be added to the mixing chamber of the microfluidic reactor at any suitable flow rate. The flow rate varies according to the internal volume and geometry of the mixing chamber. Exemplary flow rates are between 0.1 μ L/min and 10 μ L/min, such as greater than 0.1 μ L/min, greater than 0.2 μ L/min, greater than 0.3 μ L/min, greater than 0.4 μ L/min, greater than 0.5 μ L/min, greater than 0.6 μ L/min, greater than 0.7 μ L/min, greater than 0.8 μ L/min, greater than 0.9 μ L/min, greater than 1.0 μ L/min, greater than 1.1 μ L/min, greater than 1.2 μ L/min, greater than 1.3 μ L/min, greater than 1.4 μ L/min, greater than 1.5 μ L/min, greater than 1.6 μ L/min, greater than 1.7 μ L/min, greater than 1.8 μ L/min, greater than 1.9 μ L/min, greater than 2.0 μ L/min, greater than 2.1 μ L/min, greater than 2.2 μ L/min, greater than 2.3 μ L/min, greater than 2.4 μ L/min, greater than 2.5 μ L/min, greater than 2.6 μ L/min, greater than 2.7 μ L/min, greater than 2.8 μ L/min, greater than 2.9 μ L/min, greater than 3.0 μ L/min, greater than 3.25 μ L/min, greater than 3.5 μ L/min, greater than 3.75 μ L/min, greater than 4.0 μ L/min, greater than 4.5 μ L/min, greater than 5.0 μ L/min, greater than 5.5 μ L/min, greater than 6.0 μ L/min, greater than 6.5 μ L/min, greater than 7.0 μ L/min, greater than 7.5 μ L/min, greater than 8.0 μ L/min, greater than 8.5 μ L/min, greater than 9.0 μ L/min, or greater than 9.5 μ L/min. Suitable flow rates may also be up to 10. mu.L/min, up to 9.5. mu.L/min, up to 9.0. mu.L/min, up to 8.5. mu.L/min, up to 8.0. mu.L/min, up to 7.5. mu.L/min, up to 7.0. mu.L/min, up to 6.5. mu.L/min, up to 6.0. mu.L/min, up to 5.5. mu.L/min, up to 5.0. mu.L/min, up to 4.75. mu.L/min, up to 4.5. mu.L/min, up to 4.25. mu.L/min, up to 4.0. mu.L/min, up to 3.75. mu.L/min, up to 3.5. mu.L/min, up to 3.25. mu.L/min, up to 3.0. mu.L/min, up to 2.9. mu.L/min, up to 2.8. mu.L/min, up to 2.7. mu.L/min, up to 2.6., at most 2.3 μ L/min, at most 2.2 μ L/min, at most 2.1 μ L/min, at most 2.0 μ L/min, at most 1.9 μ L/min, at most 1.8 μ L/min, at most 1.7 μ L/min, at most 1.6 μ L/min, at most 1.5 μ L/min, at most 1.4 μ L/min, at most 1.3 μ L/min, at most 1.2 μ L/min, at most 1.1 μ L/min, at most 1.0 μ L/min, at most 0.9 μ L/min, at most 0.8 μ L/min, at most 0.7 μ L/min, at most 0.6 μ L/min, or at most 0.5 μ L/min. Other flow rates may also be suitable depending on the geometry and internal volume of the microfluidic reactor used. Those skilled in the art will be able to determine the appropriate flow rate based on the guidance provided herein, in combination with their knowledge in the art.

It may be important to select the appropriate molar flow rates of some of the components versus achieving the best results. The term molar flow rate ratio is defined herein. The inventors have found that the use of the correct molar flow rate ratio may in any case be critical to obtain the desired product in high yield. Thus, the molar flow rate ratio of benzophenone alcohol or substituted benzophenone alcohol to the sum of all of the one or more bases is typically 1 to at least 1, at least 1.5, or 1 to at least 1.7, especially when an (alkyl) acryloyl halide such as (alkyl) acryloyl chloride or (meth) acryloyl chloride is used. In some cases, the molar flow rate ratio of benzophenone alcohol or substituted benzophenone alcohol to the sum of all of the one or more bases can be even higher, such as 1 to at least 2, 1 to at least 2.5, or even 1 to at least 2.7. Such higher molar flow rate ratios are not required unless otherwise stated, but are generally beneficial when 3-haloalkyl carboxy halides are used as reactants.

The molar flow ratio of benzophenone alcohol or substituted benzophenone alcohol to (alkyl) acryloyl halide or 3-haloalkyl carboxy halide is generally 1 to at least 1.1. When the molar flow rate is relatively low, the amount of desired product in the product stream is generally unacceptably low. Higher molar flow rate ratios may also be used in some cases. Thus, the molar flow rate ratio of alcohol to (alkyl) acryloyl halide or 3-haloalkyl carboxy halide can be 1 to at least 1.2, 1 to at least 1.3, 1 to at least 1.4, 1 to at least 1.5, 1 to at least 1.6, 1 to at least 1.7, 1 to at least 1.8, 1 to at least 1.9, 1 to at least 2, 1 to at least 2.1, 1 to at least 2.2, 1 to at least 2.3, 1 to at least 2.4, or 1 to at least 2.5. Such higher molar flow rate ratios are not required unless otherwise specified.

When using benzophenone polyols or substituted benzophenone polyols having more than one hydroxyl group per molecule, in order to react each hydroxyl group with a molecule of (alkyl) acryloyl halide or 3-haloalkylcarboxy halide, the molar flow rate ratios discussed above can be used, except that the molar flow rate ratios will be based on the molar equivalents of hydroxyl groups rather than polyol.

In microfluidic reactors, the reaction of an alcohol and an (alkyl) acryloyl halide or 3-haloalkyl carboxy halide typically produces one or more salts of one or more bases. If these salts precipitate, they can clog microfluidic reactors leading to process failure. Thus, the polar liquid, typically water, must be present in an amount sufficient to dissolve substantially all of the salt. In this case, "substantially all" means that enough salt is dissolved so that any undissolved salt does not clog the microfluidic reactor in the process. The flow rates required to achieve this result can vary widely and depend on the volume and geometry of the microfluidic reactor used. One of ordinary skill in the art, in light of the guidelines herein, in combination with their knowledge of the art, will be able to determine the appropriate flow rate of the polar liquid (such as water) to ensure that all of the salt is dissolved. Thus, if the salt blocks the microfluidic reactor at a particular flow rate, the problem can be ameliorated in several ways. If a polar liquid is added as a solvent for the solution, for example with benzophenone alcohol or substituted benzophenone alcohol, one or more bases or both as solutes, the flow rate of the solution can be increased or the concentration of one or more solutes can be decreased. If neither is feasible, for example due to the need to maintain the proper molar flow rate ratio or other reasons, the clogging problem can be improved by using more than two addition ports and adding a polar liquid (such as water) through the third or fourth addition port. By using different addition ports for the polar liquid and the benzophenone alcohol or substituted benzophenone alcohol or base or bases, for example, the increased polar liquid flow rate can be controlled without the need to change the flow rates of the other ingredients to maintain the necessary molar flow rate ratios.

Indeed, it may be necessary to flush the microfluidic reactor before starting the reaction. The flushing step is performed again before the microfluidic reactor is taken off-line, when the process is restarted after the microfluidic reactor is taken off-line, or both. Flushing typically involves flowing a solvent (typically an organic liquid or a polar liquid as described herein) through the microfluidic reactor. The flow rate of the polar liquid during the flushing step may be any suitable flow rate, which will depend on the volume of the microfluidic reactor. The flushing step is often performed at the time of use for a period of time suitable to remove any salts, contaminants or impurities accumulated within the microfluidic reactor. This time varies depending on the volume of the microfluidic reactor, but is typically 1 minute to 1 hour, and most typically 1 minute to 15 minutes. The solvent then exits the microfluidic reactor and can be collected from the outlet. In all cases no rinsing step is required.

The painting step may also be carried out before the reaction is started. If a rinsing and painting step is employed, the painting step is typically performed after the rinsing step. The painting step generally comprises pumping benzophenone alcohol or substituted benzophenone alcohol, optionally dissolved in a polar liquid or an organic liquid, through a microfluidic reactor comprising a mixing chamber and then collecting it after it has passed through an outlet. The benzophenone alcohol or substituted benzophenone alcohol typically used in the painting step is discarded. The flow rate of the benzophenone alcohol or substituted benzophenone alcohol during the painting step can be the same as discussed above with respect to the addition of the benzophenone alcohol or substituted benzophenone alcohol during the reaction. The painting step may be carried out for any suitable length of time, typically 1 minute to 1 hour, such as 1 minute to 15 minutes.

Once any rinsing or painting steps are completed, the ingredients may be added to the mixing chamber of the microfluidic reactor under the conditions described herein and allowed to mix within the mixing chamber to form a product stream. The product stream may then exit the mixing chamber through an outlet. It is often convenient to connect a tube to the outlet. The tube may serve one or more purposes. For example, a tube may be used to cool the reaction mixture so that the space where the reaction is completed can deliver the product stream to a desired location, e.g., to collect the product or to serve as a feed to another reactor, such as another microfluidic reactor, or any combination of the foregoing. Any suitable pump may be used to pump the ingredients into the reactor. For small scale and short time operation, a syringe pump may be used. Other pumps, such as gear pumps, multiple piston pumps, etc., may be suitable for larger scale or longer run times. After a short initial start-up time, the (alkyl) acrylate product in the product stream will exit the mixing chamber of the microfluidic reactor through the outlet port while ingredients are added through the addition port.

While the reaction of benzophenone alcohol or substituted benzophenone alcohol with (alkyl) acryloyl halide or 3-haloalkyl carboxy halide is generally highly exothermic, there is generally no need to cool or otherwise adjust the temperature of the microfluidic reactor during the process described herein. Thus, the reaction can be carried out without any cooling of the microfluidic reactor, in particular without cooling of the mixing chamber of the microfluidic reactor. Instead, the process can be performed at room temperature without any temperature control of the microfluidic reactor. Room temperature is understood by the skilled artisan, but generally includes those temperatures typical for laboratory or production plant equipment, such as 20 ℃ to 25 ℃.

The product stream exiting the outlet of the microfluidic reactor typically has a polar portion and an organic portion. Because the polar liquid and the organic liquid are immiscible, the organic liquid and the polar liquid can separate into two phases in the product stream. However, in practice, when the product is a dibenzoyl (alkyl) acrylate or substituted benzoyl (alkyl) acrylate, the two phases are generally poorly defined and there is no well-defined phase boundary. This is especially true when a typical solvent such as ethyl acetate is used as the organic liquid. This may lead to two problems. First, reaction by-products, such as (alkyl) acrylic acid, which may be formed, for example, by the reaction of excess (alkyl) acryloyl halide or 3-haloalkylcarboxy halide with water when water is a polar liquid, may be present in both the polar and organic moieties. Secondly, in such cases (i.e. when the phase boundary between the phases is not significant), it may be difficult to separate the organic and polar phases, resulting in loss of product and less efficient processes.

These problems are conveniently solved by using (alkyl) acrylate compounds of formula (I). In the compounds of formula (I), R₁Is alkyl or H, and R₂Is a C1 to C12 alkyl group, optionally interrupted by one or more O atoms, and most typically interrupted by 0 or 1O atom.

In the compounds of formula (I), R₁Typically H or C1 to C4 alkyl, such as H or C1 to C2 alkyl, or even H or methyl. R₂Typically C1-C12 alkyl, such as C4-C12 alkyl, or C₄H₃An O (i.e., tetrahydrofuryl) group.

The compound of formula (I) is an (alkyl) acrylate. Surprisingly, the (alkyl) acrylates most effective in promoting phase separation are those having a relatively short R₂In particular wherein R₂Those which are C1 to C12 alkyl, optionally interrupted by one or more O atoms. R of a longer chain₂The part is less efficient. For example, when R is₂At C18, it is not as good as when R promotes a clear phase boundary₂Is effective when it is n-butyl (i.e., C4).

This result is surprising and unexpected. Those skilled in the art understand that longer chain alkyl groups are more hydrophobic than shorter chain alkyl groups, and therefore (alkyl) acrylates with longer chain alkyl groups are expected to be more effective in inducing clean phase separation and a clear phase boundary, as they will more effectively increase the hydrophobicity of the organic liquid, thereby distinguishing it from polar liquids. Surprisingly and surprisingly, this is not the case. When (alkyl) acrylates having alkyl esters greater than C12 are used, they have in fact proved less effective for this purpose than C12 or lower groups (i.e. not like the compounds of formula (I)).

Specific examples of the compound of formula (I) include methyl methacrylate, butyl acrylate, tetrahydrofuran acrylate, 2-ethylhexyl acrylate and 2-methylheptyl acrylate. Other compounds of formula (I) may also be used.

The compounds of formula (I) may be used in various ways to solve the above-mentioned phase separation problem. In a first example, a compound of formula (I) or (II) may be used as the polar liquid. In this case, the compounds of formula (I) are used to dissolve benzophenone alcohol or substituted benzophenone alcohol starting materials. The solution of benzophenone alcohol or substituted benzophenone alcohol starting material in the compound of formula (I) is then added to the mixing chamber of a microfluidic reactor as described herein.

When the compound of formula (I) is used as an organic liquid to disperse benzophenone alcohol or substituted benzophenone alcohol, the concentration of benzophenone alcohol or substituted benzophenone alcohol in the compound of formula (I) will vary depending on the solubility of benzophenone alcohol or substituted benzophenone alcohol in the compound of formula (I). In most cases, the benzophenone alcohol or substituted benzophenone alcohol will be dissolved in the compound of formula (I), and thus the concentration can be any concentration at which the benzophenone alcohol or substituted benzophenone alcohol forms a solution in the compound of formula (I). Typical concentrations are 0.01% to 30% by weight of benzophenone alcohol or substituted benzophenone alcohol. The concentration can be adjusted within the solubility limit as needed to enable the proper molar flow rate ratio of the benzophenone alcohol or substituted benzophenone alcohol to the other starting materials described herein.

Water may be added to the product stream to aid in the removal of any by-products from the organic liquid. This may be done in any suitable manner. For example, the product stream may exit the mixing chamber of the microfluidic reactor and proceed into tubing, which may then be connected to additional tubing through which water is pumped by Y or T connectors.

The organic and polar phases (the latter of which may be aqueous, especially when water washing is used) may be separated, for example, using known equipment that can be used to separate the different phases during flow. Such an apparatus may function by providing a membrane that is wettable only by one of the organic and polar phases, the latter of which may be an aqueous phase. The apparatus may provide a pressure differential across the membrane such that only the phase wetting the membrane may pass through the membrane. In a typical device, the membrane is hydrophobic and allows the organic phase to pass through.

Thus, the apparatus may function by providing an inlet for the product stream, the inlet having a combination of an organic phase and a polar phase, the latter of which may be an aqueous phase. The apparatus may also have two outlets, each outlet communicating with opposite sides of a membrane as described herein. In use, a product stream having two phases (an organic phase and a polar phase) may enter the apparatus through the inlet. One of the two phases (usually the organic phase) passes through the membrane and then exits the apparatus through a first outlet. The other phase (typically the polar phase, which may be the aqueous phase) does not pass through the membrane and then exits the apparatus through the second outlet.

Apparatus for separating the organic and polar phases as described herein are commercially available, for example, from Zaiput flow technologies, Zaiput FlowTechnologies, Cambridge, MA, USA under the trade names SEP-10, SEP-200-SS and SEP-200-HS.

In a second example using a compound of formula (I), the compound may be added to the product stream in a batch process step. In this example, the product stream is collected in a vessel to which the compound of formula (I) and optionally water are added. The amount of compound of formula (I) added should be sufficient to dissolve the collected dibenzoyl (alkyl) acrylate or substituted dibenzoyl (alkyl) acrylate reaction product. In a batch process, the organic fraction comprising an organic liquid such as ethyl acetate, dibenzoyl (alkyl) acrylate or substituted dibenzoyl (alkyl) acrylate and the compound of formula (I) is then separated from the polar liquid, which typically comprises salt, by-products and water. This can be accomplished by methods known in the art such as a separatory funnel or Dean Stark trap. Any volatile organic liquid, such as ethyl acetate, may be removed, for example, by evaporation, if desired.

In many cases, the use of a compound of formula (I) as described herein may provide one or more useful advantages. First, as described above, it can achieve good phase separation and a clear phase boundary between the organic phase and the polar phase, thereby facilitating separation of the two phases and recovery of the product from the organic phase. This clean separation also removes by-products and salts from the organic liquid, thus providing a mixture of the dibenzoyl (alkyl) acrylate or substituted dibenzoyl (alkyl) acrylate and the compound of formula (I) ready for use in a subsequent process. For example, because the compounds of formula (I) have an acrylate moiety, they may be subsequently copolymerized with dibenzoyl (alkyl) acrylates or substituted dibenzoyl (alkyl) acrylates formed in the mixing chamber of a microfluidic reactor. Thus, the product stream of the processes described herein can be fed directly to another reactor, such as a microfluidic reactor, for subsequent polymerization. When the compound of formula (I) is used as an organic liquid and the polar liquid is continuously removed as described herein in a continuous process, the reaction of the dibenzoyl (alkyl) acrylate or substituted dibenzoyl (alkyl) acrylate of the present invention with the compound of formula (I) and the subsequent polymerization can be carried out as a continuous process.

Thus, the methods described herein are considered to be industrially acceptable when the product stream comprises dibenzoyl (alkyl) acrylate or substituted dibenzoyl (alkyl) acrylate in an amount of not less than 80 wt.%, based on the total weight of the dibenzoyl (alkyl) acrylate or substituted dibenzoyl (alkyl) acrylate, unreacted starting materials, and organic by-products in the product stream (but excluding the weight of any compound of formula (I) in the product stream). The low yields are not suitable for industrial use and are considered unacceptable. In many cases, the yield is even higher, but this is not required. In some cases, the amount of dibenzoyl (alkyl) acrylate or substituted dibenzoyl (alkyl) acrylate is 85 wt.% or more, 90 wt.% or more, or even 95 wt.% or more, based in each case on the total weight of dibenzoyl (alkyl) acrylate or substituted dibenzoyl (alkyl) acrylate, unreacted starting materials, and organic by-products in the product stream (but not including the weight of any compound of formula (I) in the product stream). The weight of these components of the product stream may be measured by any suitable means, for example by gas chromatography. When gas chromatography is used, the compounds in the product stream can be determined by comparing their retention time on the same column with the retention time of a standard. The area of the peak can be calculated using standard software or even manually and then converted to concentration using a calibration curve. The calibration curve can be established by standard samples with known concentrations of the compound. Other suitable means of determining the weight% of the various components of the product stream include liquid chromatography (such as HPLC) and gas chromatography (such as GC/MS).

It is surprising that such high yields of dibenzoyl (alkyl) acrylate or substituted dibenzoyl (alkyl) acrylate can be obtained under the reaction conditions discussed herein. It is well known that (alkyl) acryloyl halides and 3-haloalkyl carboxyl halides are highly reactive with polar liquids such as water to provide the corresponding acids. Although it is expected that the presence of a polar liquid such as water will rapidly hydrolyze the (alkyl) acryloyl halide or 3-haloalkyl carboxy halide, the process described herein uses a polar liquid, typically water, but surprisingly hydrolysis is not the predominant reaction and high yields of product can be achieved. Furthermore, it is known that the reaction between (alkyl) acryloyl halides or 3-haloalkylcarboxy halides is highly exothermic, thus requiring external cooling to avoid dangerous heat release, unwanted side reactions, or both. Surprisingly, the process disclosed herein can be carried out at high yield even at room temperature and without the use of a cooling device of a microfluidic reactor.

List of exemplary embodiments

The following list illustrates specific embodiments of the present disclosure, but is not intended to be limiting. Other embodiments not shown herein are also contemplated.

1. A method of preparing a dibenzoyl (alkyl) acrylate or a substituted dibenzoyl (alkyl) acrylate, the method comprising:

the following were added to the mixing chamber of the microfluidic reactor:

a benzophenone alcohol or a substituted benzophenone alcohol comprising at least one hydroxyl moiety,

one or more bases sufficient to at least partially deprotonate the benzophenone alcohol or substituted benzophenone alcohol,

a polar liquid, which is a liquid having a polarity,

(alkyl) acryloyl halide or 3-haloalkylcarboxy halide, and

an organic liquid immiscible with the polar liquid in an amount sufficient to dissolve the (alkyl) acryloyl halide or 3-haloalkyl carboxy halide, wherein

(ii) a molar flow rate ratio of all hydroxyl moieties to the sum of all of the one or more bases of 1 to at least 1.1; and

producing a product stream comprising one or more dibenzoyl (alkyl) acrylates or substituted dibenzoyl (alkyl) acrylates and one or more salts of the one or more bases; and wherein

The polar liquid added to the mixing chamber is sufficient to dissolve the one or more salts; and is

The product stream has an organic portion and a polar portion, the organic portion of the product stream comprising dibenzoyl (alkyl) acrylate or substituted dibenzoyl (alkyl) acrylate in an amount of at least 80 wt% based on the total weight of dibenzoyl (alkyl) acrylate or substituted dibenzoyl (alkyl) acrylate, unreacted benzophenone alcohol or substituted benzophenone alcohol, and organic byproducts in the product stream; and wherein further comprising any of the following:

(a) the organic liquid comprises a compound of formula (I); or

(b) The process further comprises adding a compound of formula (I) to the product stream; or

(c) The organic liquid comprises a compound of formula (I), and the method further comprises combining a compound of formula (I)

Adding the product into the product stream

Wherein

R₁Is H or C1-C4 alkyl; and is

R₂Is a C1 to C12 alkyl group optionally interrupted with one or more O atoms.

2. A method of preparing a dibenzoyl (alkyl) acrylate or a substituted dibenzoyl (alkyl) acrylate, the method comprising:

the following were added to the mixing chamber of the microflow reactor:

a benzophenone alcohol or a substituted benzophenone alcohol comprising at least one hydroxyl moiety,

one or more bases sufficient to at least partially deprotonate the benzophenone alcohol or substituted benzophenone alcohol,

a polar liquid, which is a liquid having a polarity,

(alkyl) acryloyl halide or 3-haloalkylcarboxy halide, and

an organic liquid immiscible with the polar liquid in an amount sufficient to dissolve the (alkyl) acryloyl halide or 3-haloalkyl carboxy halide, wherein

(ii) a molar flow rate ratio of all hydroxyl moieties to the sum of all of the one or more bases of 1 to at least 1.1; and

producing a product stream comprising one or more dibenzoyl (alkyl) acrylates or substituted dibenzoyl (alkyl) acrylates and one or more salts of the one or more bases; and wherein

The polar liquid added to the mixing chamber is sufficient to dissolve the one or more salts; and is

The product stream has an organic portion and a polar portion, the organic portion of the product stream comprising dibenzoyl (alkyl) acrylate or substituted dibenzoyl (alkyl) acrylate in an amount of at least 80 wt% based on the total weight of dibenzoyl (alkyl) acrylate or substituted dibenzoyl (alkyl) acrylate, unreacted benzophenone alcohol or substituted benzophenone alcohol, and organic byproducts in the product stream;

the method is characterized by any of the following:

(a) the organic liquid comprises a compound of formula (I); or

(b) The process further comprises adding a compound of formula (I) to the product stream; or

(c) The organic liquid comprises a compound of formula (I), and the process further comprises adding the compound of formula (I) to the product stream

Wherein

R₁Is H or C1-C4 alkyl; and is

R₂Is a C1 to C12 alkyl group optionally interrupted with one or more O atoms.

3. The method of any one of the preceding embodiments, wherein the organic liquid comprises a compound of formula (I).

4. The process according to any one of the preceding embodiments, wherein the process further comprises adding a compound of formula (I) to the product stream.

5. The method of any one of the preceding embodiments, wherein the amount of dibenzoyl (alkyl) acrylate or substituted dibenzoyl (alkyl) acrylate in the product stream is at least 85 wt%, based on the total weight of dibenzoyl (alkyl) acrylate or substituted dibenzoyl (alkyl) acrylate, unreacted benzophenone alcohol or substituted benzophenone alcohol, and organic byproducts in the product stream.

6. The method of any one of the preceding embodiments, wherein the amount of dibenzoyl (alkyl) acrylate or substituted dibenzoyl (alkyl) acrylate in the product stream is at least 90 wt%, based on the total weight of dibenzoyl (alkyl) acrylate or substituted dibenzoyl (alkyl) acrylate, unreacted benzophenone alcohol or substituted benzophenone alcohol, and organic byproducts in the product stream.

7. The method of any one of the preceding embodiments, wherein the amount of dibenzoyl (alkyl) acrylate or substituted dibenzoyl (alkyl) acrylate in the product stream is at least 95 wt%, based on the total weight of dibenzoyl (alkyl) acrylate or substituted dibenzoyl (alkyl) acrylate, unreacted benzophenone alcohol or substituted benzophenone alcohol, and organic byproducts in the product stream.

8. The method according to any one of the preceding embodiments, wherein the polar liquid comprises water, methanol, ethanol, propanol, or mixtures thereof.

9. The method of any one of the preceding embodiments, wherein the polar liquid comprises water.

10. The method of any one of the preceding embodiments, wherein the polar liquid is water.

11. The method of embodiment 10, wherein the water is deionized, distilled or reverse osmosis water.

12. The method of any one of the preceding embodiments, wherein the benzophenone alcohol or substituted benzophenone alcohol is a monohydric alcohol having only one hydroxyl group.

13. The method according to any one of embodiments 1 to 11, wherein the benzophenone alcohol or substituted benzophenone alcohol is a polyol having more than one hydroxyl group.

14. The method of any one of the preceding embodiments, wherein the benzophenone alcohol or substituted benzophenone alcohol is 4-hydroxybenzophenone, 4-hydroxyethylbenzophenone, 2-hydroxybenzophenone, 3-hydroxybenzophenone, 4-alcohol 4' -hydroxybenzophenone, 5-bromo 2-hydroxybenzophenone, 5-chloro 2-hydroxybenzophenone, and the like.

15. The method of any one of the preceding embodiments, wherein the benzophenone alcohol is 4-hydroxybenzophenone.

16. The method of any one of the preceding embodiments, wherein the one or more bases comprise at least one of: triethylamine, dimethylamine, trimethylamine, methyldiethylamine, alkali metal hydroxides and alkaline earth metal hydroxides.

17. The method of any one of the preceding embodiments, wherein the one or more bases comprise triethylamine.

18. The method of any one of the preceding embodiments, wherein the one or more bases comprise potassium hydroxide, sodium hydroxide, or a mixture thereof.

19. The method of any one of the preceding embodiments, further comprising the step of adding water to the product stream.

20. The method of embodiment 19, wherein water is added to the product stream in a continuous manner after the product stream exits the outlet of the mixing chamber of the microfluidic reactor.

21. The method of any one of embodiments 19 to 20, wherein the water added to the product stream is distilled, deionized, or reverse osmosis water.

22. The method of any one of embodiments 19 to 21, wherein the polar portion and the organic portion of the product stream are continuously separated.

23. The method of embodiment 22, wherein the step of continuously separating the polar fraction comprises passing the product stream through an apparatus comprising:

a membrane wettable by only one of the polar phase or the organic phase, and

pressure difference across the membrane

Only one of the polar or organic portions is passed through the membrane, separating the polar portion from the organic portion of the product stream.

24. The method of any one of the preceding embodiments, wherein the step of adding benzophenone alcohol or substituted benzophenone alcohol to the mixing chamber of the microfluidic reactor comprises adding a second alcohol to the mixing chamber of the microfluidic reactor.

25. The method of any one of embodiments 1-24, wherein the step of adding benzophenone alcohol or substituted benzophenone alcohol to the mixing chamber of the microfluidic reactor comprises adding only one type of benzophenone alcohol or substituted benzophenone alcohol and no other alcohol to the mixing chamber of the microfluidic reactor.

26. The method of any one of the preceding embodiments, wherein the step of adding the benzophenone alcohol or substituted benzophenone alcohol to the mixing chamber of the microfluidic reactor comprises adding a solution of the benzophenone alcohol or substituted benzophenone alcohol in a polar liquid to the mixing chamber of the microfluidic reactor.

27. The method of any one of the preceding embodiments, wherein the organic liquid comprises one or more of: dichloromethane, ethyl acetate, butyl acetate, methyl ethyl ketone, methyl butyl ketone or one or more compounds of formula (I).

28. The method of embodiment 27, wherein the organic liquid comprises one or more compounds of formula (I).

29. The method of embodiment 27, wherein the organic liquid is one or more compounds of formula (I).

30. The method according to any one of the preceding embodiments, wherein in the compound of formula (I), R₂Is C1-C12 alkyl.

31. The method according to any one of the preceding embodiments, wherein R is₁Is methyl or H.

32. The method of embodiment 31, wherein R₁Is methyl.

33. The method of embodiment 31, wherein R₁Is H.

34. The method according to any one of the preceding embodiments, wherein R is₂Is C1.

35. The method according to any one of embodiments 1-33, wherein R₂Is C2.

36. The method according to any one of embodiments 1-33, wherein R₂Is C3.

37. The method according to any one of embodiments 1-33, wherein R₂Is C4.

38. The method according to any one of embodiments 1-33, wherein R₂Is C5.

39. The method according to any one of embodiments 1-33, wherein R₂Is C6.

40. The method according to any one of embodiments 1-33, wherein R₂Is C7.

41. The method according to any one of embodiments 1-33, wherein R₂Is C8.

42. The method according to any one of embodiments 1-33, wherein R₂Is C9.

43. The method according to any one of embodiments 1-33, wherein R₂Is C10.

44. The method according to any one of embodiments 1-33, wherein R₂Is C11.

45. The method according to any one of embodiments 1-33, wherein R₂Is C12.

46. The method according to any one of embodiments 1-33, wherein R₂Is 2-ethylhexanol.

47. The method according to any one of embodiments 1-33, wherein R₂Is 2-methyl heptanol.

48. The method of any one of the preceding embodiments, wherein the (alkyl) acryloyl halide or 3-haloalkylcarboxyl halide is an (alkyl) acryloyl halide.

49. The method of embodiment 48 wherein the (alkyl) acryloyl halide comprises a C10 or smaller alkyl group.

50. The method of embodiment 48 wherein the (alkyl) acryloyl halide comprises a C9 or smaller alkyl group.

51. The method of embodiment 48 wherein the (alkyl) acryloyl halide comprises a C8 or smaller alkyl group.

52. The method of embodiment 48 wherein the (alkyl) acryloyl halide comprises a C7 or smaller alkyl group.

53. The method of embodiment 48 wherein the (alkyl) acryloyl halide comprises a C6 or smaller alkyl group.

54. The method of embodiment 48 wherein the (alkyl) acryloyl halide comprises a C5 or smaller alkyl group.

55. The method of embodiment 48 wherein the (alkyl) acryloyl halide comprises a C4 or smaller alkyl group.

56. The method of embodiment 48 wherein the (alkyl) acryloyl halide comprises a C3 or smaller alkyl group.

57. The method of embodiment 48 wherein the (alkyl) acryloyl halide comprises a C2 or smaller alkyl group.

58. The method according to embodiment 48, wherein the (alkyl) acryloyl halide is an acryloyl halide or a methacryloyl halide.

59. The process according to embodiments 48 to 58, wherein the halide of the (alkyl) acryloyl halide is chloride.

60. The method according to any one of the preceding embodiments, wherein the (alkyl) acryloyl halide is acryloyl chloride or methacryloyl chloride.

61. The method according to any one of the preceding embodiments, wherein the (alkyl) acryloyl halide is acryloyl chloride.

62. The process according to any one of embodiments 1 to 60, wherein the (alkyl) acryloyl halide is methacryloyl chloride.

63. The process of any one of embodiments 1 to 47, wherein the (alkyl) acryloyl halide or 3-haloalkylcarboxy halide is a 3-haloalkylcarboxy halide.

64. The method of embodiment 63, wherein the halogen group of the 3-haloalkylcarboxyhalide is chloro.

65. The method of embodiment 63 or 64 wherein the haloalkyl group is C30 or less.

66. The method of embodiment 63 or 64 wherein the haloalkyl group is C30 or less.

67. The method of embodiment 63 or 64 wherein the haloalkyl group is C24 or less.

68. The method of embodiment 63 or 64 wherein the haloalkyl group is C22 or less.

69. The method of embodiment 63 or 64 wherein the haloalkyl group is C20 or less.

70. The method of embodiment 63 or 64 wherein the haloalkyl group is C18 or less.

71. The method of embodiment 63 or 64 wherein the haloalkyl group is C16 or less.

72. The method of embodiment 63 or 64 wherein the haloalkyl group is C12 or less.

73. The method of embodiment 63 or 64 wherein the haloalkyl group is C10 or less.

74. The method of embodiment 63 or 64 wherein the haloalkyl group is C8 or less.

75. The method of embodiment 63 or 64 wherein the haloalkyl group is C7 or less.

76. The method of embodiment 63 or 64 wherein the haloalkyl group is C6 or less.

77. The method of embodiment 63 or 64 wherein the haloalkyl group is C5 or less.

78. The method of embodiment 63 or 64 wherein the haloalkyl group is C4 or less.

79. The method of embodiment 63 or 64 wherein the haloalkyl group is C3 or less.

80. The method of any one of the preceding embodiments, wherein the halide of the 3-haloalkylcarboxy halide is chloride.

81. The method of any one of the preceding embodiments, wherein the 3-haloalkylcarboxy halide is 3-chloropropionyl chloride.

82. The method of any one of the preceding embodiments, wherein the step of adding the benzophenone alcohol or substituted benzophenone alcohol to the mixing chamber of the microfluidic reactor comprises adding a mixture of the benzophenone alcohol or substituted benzophenone alcohol and at least one of the one or more bases to the mixing chamber of the microfluidic reactor.

83. The method of embodiment 82, wherein a mixture of benzophenone alcohol or substituted benzophenone alcohol and at least one of the one or more bases is added as a solution to the polar liquid.

84. The method of any one of the preceding embodiments, wherein the step of adding benzophenone alcohol or substituted benzophenone alcohol to the mixing chamber of the microfluidic reactor comprises adding benzophenone alcohol or substituted benzophenone alcohol to the mixing chamber of the microfluidic reactor through a first addition port.

85. The method of any one of the preceding embodiments, wherein the step of adding the (alkyl) acryloyl halide or the 3-haloalkylcarboxy halide to the mixing chamber of the microfluidic reactor comprises adding the (alkyl) acryloyl halide or the 3-haloalkylcarboxy halide to the mixing chamber of the microfluidic reactor through a second addition port.

86. The method of any one of the preceding embodiments, wherein the step of adding benzophenone alcohol or substituted benzophenone alcohol to the mixing chamber of the microfluidic reactor comprises adding a mixture of benzophenone alcohol or substituted benzophenone alcohol, a polar liquid, and the one or more bases to the mixing chamber of the microfluidic reactor through a first addition port.

87. The method of any one of the preceding embodiments, wherein the step of adding the (alkyl) acryloyl halide or the 3-haloalkylcarboxy halide to the mixing chamber of the microfluidic reactor comprises adding a solution of the (alkyl) acryloyl halide or the 3-haloalkylcarboxy halide in the organic liquid to the mixing chamber of the microfluidic reactor through a second addition port.

88. The process of any one of the preceding embodiments, wherein the molar flow ratio of benzophenone alcohol or substituted benzophenone alcohol to (alkyl) acryloyl halide or 3-haloalkylcarboxy halide is 1 to at least 1.1.

89. The process of any one of the preceding embodiments, wherein the molar flow ratio of benzophenone alcohol or substituted benzophenone alcohol to (alkyl) acryloyl halide or 3-haloalkylcarboxy halide is 1 to at least 1.2.

90. The process of any one of the preceding embodiments, wherein the molar flow ratio of benzophenone alcohol or substituted benzophenone alcohol to (alkyl) acryloyl halide or 3-haloalkylcarboxy halide is 1 to at least 1.3.

91. The process of any one of the preceding embodiments, wherein the molar flow ratio of benzophenone alcohol or substituted benzophenone alcohol to (alkyl) acryloyl halide or 3-haloalkylcarboxy halide is 1 to at least 1.4.

92. The process of any one of the preceding embodiments, wherein the molar flow ratio of benzophenone alcohol or substituted benzophenone alcohol to (alkyl) acryloyl halide or 3-haloalkylcarboxy halide is 1 to at least 1.5.

93. The process of any one of the preceding embodiments, wherein the molar flow ratio of benzophenone alcohol or substituted benzophenone alcohol to (alkyl) acryloyl halide or 3-haloalkylcarboxy halide is 1 to at least 1.6.

94. The process of any one of the preceding embodiments, wherein the molar flow ratio of benzophenone alcohol or substituted benzophenone alcohol to (alkyl) acryloyl halide or 3-haloalkylcarboxy halide is 1 to at least 1.7.

95. The process of any one of the preceding embodiments, wherein the molar flow ratio of benzophenone alcohol or substituted benzophenone alcohol to (alkyl) acryloyl halide or 3-haloalkylcarboxy halide is 1 to at least 1.8.

96. The process of any one of the preceding embodiments, wherein the molar flow ratio of benzophenone alcohol or substituted benzophenone alcohol to (alkyl) acryloyl halide or 3-haloalkylcarboxy halide is 1 to at least 1.9.

97. The process of any one of the preceding embodiments, wherein the molar flow ratio of benzophenone alcohol or substituted benzophenone alcohol to (alkyl) acryloyl halide or 3-haloalkylcarboxy halide is 1 to at least 2.0.

98. The process of any one of the preceding embodiments, wherein the molar flow ratio of benzophenone alcohol or substituted benzophenone alcohol to (alkyl) acryloyl halide or 3-haloalkylcarboxy halide is 1 to at least 2.1.

99. The process of any one of the preceding embodiments, wherein the molar flow ratio of benzophenone alcohol or substituted benzophenone alcohol to (alkyl) acryloyl halide or 3-haloalkylcarboxy halide is 1 to at least 2.2.

100. The process of any one of the preceding embodiments, wherein the molar flow ratio of benzophenone alcohol or substituted benzophenone alcohol to (alkyl) acryloyl halide or 3-haloalkylcarboxy halide is 1 to at least 2.3.

101. The process of any one of the preceding embodiments, wherein the molar flow ratio of benzophenone alcohol or substituted benzophenone alcohol to (alkyl) acryloyl halide or 3-haloalkylcarboxy halide is 1 to at least 2.4.

102. The process of any one of the preceding embodiments, wherein the molar flow ratio of benzophenone alcohol or substituted benzophenone alcohol to (alkyl) acryloyl halide or 3-haloalkylcarboxy halide is 1 to at least 2.5.

103. The process of any one of the preceding embodiments, wherein the molar flow ratio of benzophenone alcohol or substituted benzophenone alcohol to the sum of all of the at least one base is 1 to at least 1.5.

104. The process of any one of the preceding embodiments, wherein the molar flow ratio of benzophenone alcohol or substituted benzophenone alcohol to the sum of all of the at least one base is from 1 to at least 1.8.

105. The process of any one of the preceding embodiments, wherein the molar flow ratio of benzophenone alcohol or substituted benzophenone alcohol to the sum of all of the at least one base is 1 to at least 1.9.

106. The process of any one of the preceding embodiments, wherein the molar flow ratio of benzophenone alcohol or substituted benzophenone alcohol to the sum of all of the at least one base is 1 to at least 2.0.

107. The process of any one of the preceding embodiments, wherein the molar flow ratio of benzophenone alcohol or substituted benzophenone alcohol to the sum of all of the at least one base is from 1 to at least 2.1.

108. The process of any one of the preceding embodiments, wherein the molar flow ratio of benzophenone alcohol or substituted benzophenone alcohol to the sum of all of the at least one base is 1 to at least 2.2.

109. The process of any one of the preceding embodiments, wherein the molar flow ratio of benzophenone alcohol or substituted benzophenone alcohol to the sum of all of the at least one base is from 1 to at least 2.3.

110. The process of any one of the preceding embodiments, wherein the molar flow ratio of benzophenone alcohol or substituted benzophenone alcohol to the sum of all of the at least one base is from 1 to at least 2.4.

111. The process of any one of the preceding embodiments, wherein the molar flow ratio of benzophenone alcohol or substituted benzophenone alcohol to the sum of all of the at least one base is from 1 to at least 2.5.

112. A method according to any one of the preceding embodiments, wherein the microfluidic reactor is not temperature controlled during the method.

113. The method of any one of the preceding embodiments, wherein the mixing chamber of the microfluidic reactor has an internal volume of no more than 5 mL.

114. The method of any one of the preceding embodiments, wherein the mixing chamber of the microfluidic reactor has an internal volume of no more than 1 mL.

115. The method of any one of the preceding embodiments, wherein the mixing chamber of the microfluidic reactor has an internal volume of no more than 800 μ L.

116. The method of any one of the preceding embodiments, wherein the mixing chamber of the microfluidic reactor has an internal volume of no more than 750 μ L.

117. The method of any one of the preceding embodiments, wherein the mixing chamber of the microfluidic reactor has an internal volume of no more than 600 μ L.

118. The method of any one of the preceding embodiments, wherein the mixing chamber of the microfluidic reactor has an internal volume of no more than 500 μ L.

119. The method of any one of the preceding embodiments, wherein the mixing chamber of the microfluidic reactor has an internal volume of no more than 400 μ L.

120. The method of any one of the preceding embodiments, wherein the mixing chamber of the microfluidic reactor has an internal volume of no more than 300 μ L.

121. The method of any one of the preceding embodiments, wherein the mixing chamber of the microfluidic reactor has an internal volume of no more than 250 μ L.

122. The method of any one of the preceding embodiments, wherein the mixing chamber of the microfluidic reactor has an internal volume of no more than 200 μ L.

123. The method of any one of the preceding embodiments, wherein the mixing chamber of the microfluidic reactor has an internal volume of no more than 100 μ L.

124. The method of any one of the preceding embodiments, wherein the mixing chamber of the microfluidic reactor has an internal volume of no more than 50 μ L.

125. The method according to any one of the preceding embodiments, wherein the method further comprises a rinsing step occurring prior to the adding step, the rinsing step comprising flowing a rinsing solvent through the mixing chamber of the microfluidic reactor and out the outlet.

126. The method of embodiment 125, wherein the rinsing solvent comprises water, ethanol, propanol, or a mixture thereof.

127. The method of embodiment 126, wherein the flushing solvent is water.

128. The method of embodiment 125 wherein the flush solvent is selected to be the same as the polar liquid.

129. The method according to any one of the preceding embodiments, wherein the method further comprises a painting step occurring prior to the adding step, the painting step comprising flowing an alcohol through the mixing chamber of the microfluidic reactor and out the outlet.

130. The method of embodiment 129, wherein the painting step consists of: a solution of benzophenone alcohol or substituted benzophenone alcohol is flowed through the mixing chamber of the microfluidic reactor and out the outlet.

131. The method of any of embodiments 129 to 130, wherein the painting step occurs after the rinsing step.

132. The method of embodiment 131, wherein the rinsing step is the rinsing step of any one of embodiments 125-128.

133. The method of any one of the preceding embodiments, wherein the microfluidic reactor is an impinging flow reactor.

134. The method according to any one of the preceding embodiments, wherein the microfluidic reactor is not cooled by a cooling device.

135. The method of any one of the preceding embodiments, wherein the mixing chamber of the microfluidic reactor is not cooled by a cooling device.

136. The method according to any one of the preceding embodiments, wherein the method is performed at room temperature.

137. The method of any one of the preceding embodiments, wherein: the mixing chamber of the microfluidic reactor comprises an outlet; and wherein the process further comprises the step of removing the (alkyl) acrylate from the outlet simultaneously with the adding step.