CN112028758A

CN112028758A - Process for the preparation of hydroxyaldehydes and process for resolving optical isomers using electrodialysis techniques

Info

Publication number: CN112028758A
Application number: CN202011031660.8A
Authority: CN
Inventors: 刘文杰; 陆成梁; 陈彦; 邱贵森; 苏金环; 曾聪明; 蒋泰隆
Original assignee: Guang'an Mojia Biotechnology Co ltd
Current assignee: Guang'an Mojia Biotechnology Co ltd
Priority date: 2020-05-25
Filing date: 2020-09-27
Publication date: 2020-12-04
Anticipated expiration: 2040-09-27
Also published as: CN112028758B

Abstract

Provided herein is a method for preparing a hydroxyaldehyde using an immobilized catalyst, wherein the immobilized catalyst comprises a solid support and a tertiary amine-based functional group. The present application also provides a method of making polyhydroxy alcohol compounds and polyhydroxy acid compounds. The present application also provides a method for resolving optical isomers from racemates by electrodialysis.

Description

Process for the preparation of hydroxyaldehydes and process for resolving optical isomers using electrodialysis techniques

Technical Field

The present application is in the field of chemistry and chemical engineering and relates generally to methods for preparing hydroxyaldehydes, polyhydroxy alcohol compounds, and polyhydroxy acid compounds, and for resolving optical isomers from racemates using biocatalytic and electrodialysis techniques.

Background

Hydroxypivalaldehyde (also known as 2, 2-dimethyl-3-hydroxypropanal, abbreviated as HPA) is an important intermediate for synthesizing various fine chemicals, and is mainly used as a raw material and a modifier for synthesizing spiroglycol, neopentyl glycol, polyurethane and polyacrylate, and an intermediate for synthesizing chemicals such as an extractant, an insecticide, VB5 and the like. HPA can generate hydroxypivalyl alcohol through hydrogenation (reduction) and hydroxypivalic acid (or hydroxypivalic acid) through oxidation, and the hydroxypivalyl alcohol and the hydroxypivalic acid are important intermediates for chemical production and are widely applied to the aspects of lubricants, dyes, medicines, pesticides and the like.

At present, most of HPA produced at home and abroad is obtained by taking formaldehyde and isobutyraldehyde as starting raw materials through aldol condensation reaction. The screening of aldol condensation reaction catalyst is the key point of HPA synthesis, in the prior art, strong alkali such as sodium hydroxide (potassium) is selected as the catalyst, and the alkalinity is too strong, so that condensation reaction byproducts are more, the generated HPA water solution contains more impurities, and the product purity is lower. US3920760 reports that 25% sodium carbonate as catalyst can reduce the formation of by-products, but neopentyl glycol and other impurities remain high, and the reaction time is long and the amount of catalyst used is large. However, these catalysts all have the same problem that they cannot be separated from the aqueous HPA product solution. HPA is a high-activity intermediate, the stability of HPA is influenced by acid and alkali, and equipment is easily corroded by the presence of inorganic alkali. Thus, the presence of the catalyst adversely affects the storage, transport and subsequent use of the HPA.

In addition, chirality is an essential attribute of nature, and many biological macromolecules and biologically active substances have chiral characteristics. Although the chemical components of two or more different configurations of the chiral substance are completely the same, the physiological activities are often different, only one configuration usually has the required activity, and the other configurations have little or no effect and even have toxic or side effects. Such as pantothenic acid (pantothenic acid), also known as bendocinic acid, is one of the vitamins of the B group, is a component of coenzyme A, is involved in the metabolism of proteins, fats and sugars, and plays an important role in substance metabolism. The active ingredient is D-configuration D-pantothenic acid (vitamin B5), but because of its instability, it is mainly available in the form of calcium D-pantothenate.

Resolution is one of the main routes of acquisition of optically pure chiral compounds. Compared with the traditional chemical resolution method, the enzymatic resolution method does not need to use a resolution reagent with high price, has mild reaction conditions, good optical selectivity and environmental friendliness, and can also carry out reactions which cannot be carried out by a chemical method. The enzyme method separation is more and more advocated by scientific researchers of various countries by virtue of the obvious advantages of the enzyme method separation, and has already been subjected to a plurality of industrial success cases.

For example, D-Pantolactone (D-Pantolactone) is an important chiral intermediate for the production of the pantothenic acid series, such as calcium D-pantothenate, D-panthenol, and D-pantethine. At present, the industrial synthesis of D-pantoic acid lactone mostly adopts a technical route combining a chemical method and a hydrolytic enzyme resolution method. Namely, racemic DL-pantoic acid lactone is produced by a chemical method, then D-pantoic acid lactone hydrolase is used for hydrolysis and resolution, the clear liquid of the resolution reaction is firstly extracted by an organic solvent to obtain the L-pantoic acid lactone and unreacted D-pantoic acid lactone, and the water phase (containing D-pantoic acid) is added with acid for lactonization and then is extracted by the organic solvent, and then desalinization and decoloration are carried out, and the product is refined by a recrystallization method. For example, in CN1313402A, DL-pantoic acid lactone is resolved by using free or immobilized cells, then dichloromethane is used for extraction, aqueous phase hydrochloric acid is used for acidification and then dichloromethane is used for extraction, and D-pantoic acid lactone crude product obtained after solvent recovery is recrystallized in acetone/isopropyl ether to obtain qualified D-pantoic acid lactone. The process has the disadvantages of low yield and high cost, for example, a large amount of organic solvent is used for extraction in the process of extracting and refining D-pantoic acid obtained by enzyme reaction, which causes environmental and cost problems, and the crude D-pantoic acid lactone is required to be recrystallized and refined.

Thus, there is a need for improved methods for the preparation of hydroxyaldehydes, particularly HPA, polyhydroxy alcohol compounds, and polyhydroxy acid compounds, and for the resolution of optical isomers from racemates.

Summary of The Invention

In one aspect, the present application provides a method for resolving optical isomers from racemates by electrodialysis, comprising:

(a) subjecting aldehydes to an aldol condensation reaction in the presence of a first catalyst to obtain hydroxyaldehydes, wherein at least one of the aldehydes is an aldehyde having an alpha-H, the first catalyst being an immobilized catalyst comprising a solid support and a tertiary amine-based functional group;

(b) reacting the hydroxyaldehyde obtained in the step (a) with cyanide under an acidic condition to form a lactone racemate;

(c) reacting the lactone racemate obtained in step (b) in the presence of a second catalyst to form a mixture comprising an ionizable form of the first optical isomer and a non-ionizable form of the second optical isomer;

(d) subjecting the mixture obtained in step (c) to an electrodialysis treatment to allow the ionizable form of the first optical isomer and the non-ionizable form of the second optical isomer to be separated; and

(e) collecting the separated ionizable form of the first optical isomer, and/or collecting the separated nonionized form of the second optical isomer.

In some embodiments, the second catalyst comprises an enzyme composition. In some embodiments, the enzyme composition comprises an ester hydrolase. In some embodiments, the enzyme composition contains a purified enzyme, a cell expressing an enzyme, or a lysate of a cell expressing an enzyme. In some embodiments, the enzyme composition is immobilized on a substrate.

In some embodiments, after step (c) and before step (d), further comprising: removing the residue of the second catalyst in the mixture.

In some embodiments, the methods of resolving optical isomers from racemates by electrodialysis described herein further comprise purifying and/or concentrating the ionizable form of the separated first optical isomer, and/or purifying and/or concentrating the non-ionizable form of the separated second optical isomer.

In some embodiments, the methods of resolving an optical isomer from a racemate by electrodialysis, as described herein, further comprise converting the non-ionized form of the second optical isomer into the racemate.

In some embodiments, the electrodialysis treatment is performed in an electrodialysis cell having a depleting compartment and a concentrating compartment separated by an ion exchange membrane. In some embodiments, the electrodialysis treatment comprises placing the mixture in the depletion compartment and a solvent in the concentration compartment, and by energizing the electrodialysis cell, the ionizable form of the first optical isomer in the depletion compartment migrates into the solvent in the concentration compartment.

In some embodiments, the solvent comprises pure water. In some embodiments, the ion exchange membrane is a homogeneous membrane or a heterogeneous membrane. In some embodiments, the electrodialysis treatment is performed in one electrodialysis cell, or in more than one electrodialysis cell in series.

In some embodiments, the racemate is DL-pantoic acid lactone, the ionizable form of the first optical isomer is D-pantoic acid, and the nonionized form of the second optical isomer is L-pantoic acid lactone.

In another aspect, the present application provides a method of making a polyhydroxy alcohol compound, comprising:

(b) hydrogenating the hydroxyaldehyde obtained in step (a) to form a polyhydroxyl alcohol compound.

In some embodiments, the polyol compound is neopentyl glycol. In some embodiments, the aldehyde comprises or consists of formaldehyde and isobutyraldehyde.

In another aspect, the present application provides a method of preparing a polyhydroxy acid compound, comprising:

(b) oxidizing the hydroxyaldehyde obtained in step (a) to form a polyhydroxy acid compound.

In some embodiments, the polyhydroxy acid compound is hydroxypentanoic acid. In some embodiments, the aldehyde comprises or consists of formaldehyde and isobutyraldehyde.

In another aspect, the present application provides a method for preparing hydroxyaldehydes, said method comprising subjecting an aldehyde to an aldol condensation reaction (also referred to as an "aldol condensation reaction") in the presence of a first catalyst to obtain the hydroxyaldehyde, wherein at least one of said aldehydes is an aldehyde having α -H, said first catalyst is an immobilized catalyst comprising a solid support and a tertiary amine-based functional group.

In some embodiments, the aldehyde comprises formaldehyde and another aldehyde. In some embodiments, the other aldehyde is selected from the group consisting of: acetaldehyde, propionaldehyde, n-butyraldehyde, isobutyraldehyde, pivalaldehyde, isovaleraldehyde, hexanal, octanal, 2-methylbutyraldehyde, 2-methylvaleraldehyde, 3-methylvaleraldehyde, 4-methylvaleraldehyde, glutaraldehyde, and any combination thereof. In some embodiments, the aldehyde comprises or consists of formaldehyde and isobutyraldehyde.

In some embodiments, the hydroxyaldehyde is selected from the group consisting of: dimethylolaldehyde, trimethylolacetaldehyde, 3-hydroxypropanal, 3-hydroxybutyraldehyde, 3-hydroxypentanal, 3-hydroxy-2-methylbutyraldehyde, 3-hydroxy-2-methylpentanal, 3-hydroxy-2-ethylhexanal, hydroxypivalaldehyde, and any combination thereof. In some embodiments, the hydroxyaldehyde is hydroxypivalaldehyde.

In some embodiments, the solid support is selected from the group consisting of: resins and inorganic or organic materials comprising carbon, silicon or aluminum. In some embodiments, the solid support is capable of withstanding temperatures above 60 ℃.

In some embodiments, the resin is subjected to a wash regeneration while the catalytic reaction is in progress. In some embodiments, the resin is selected from the group consisting of: styrene resins, polyarylethersulfone resins, silicone resins, epoxy resins, polyester resins, phenolic resins, alkyd resins, nitrocellulose, amino resins, acrylic resins, and polyurethane resins.

In some embodiments, the immobilized catalyst is selected from the group consisting of: photosensitive polyarylether containing tertiary amine functional groups on side chains, dimethylaminoethyl methacrylate-acrylonitrile copolymer, PSF-g-PDMAEMA and Si-MCM-41 tertiary amine carbon dioxide absorption film solid catalyst. In some embodiments, the structures of the photosensitive polyarylether having tertiary amine functional groups in its side chains, the dimethylaminoethyl methacrylate-acrylonitrile copolymer and the PSF-g-PDMAEMA solid catalyst are respectively:

in some embodiments, the immobilized catalyst is selected from the group consisting of: 270 resin with N, N-dimethylanilinium groups attached, 607 resin with N, N-dimethylanilinium groups attached, Merrifield resin with ethylpiperazine attached.

In some embodiments, the tertiary amine functional group is selected from the group consisting of: trimethylamine, triethylamine, tri-N-propylamine, tri-N-butylamine, methyldiethylamine, methyldiisopropylamine, dimethyl-t-butylamine, N' -tetramethylethylenediamine, and any combination thereof.

In some embodiments, the tertiary amine functional group is covalently attached to the solid support. In some embodiments, the tertiary amine functional group is covalently attached to the solid support via a linker. In some embodiments, the linker is an aromatic group (optionally, phenyl), a saturated carbon chain, an ester chain, or a carbon ether chain.

In some embodiments, the aldehyde is premixed prior to contacting with the immobilized catalyst for aldol condensation reaction. In some embodiments, the reaction is carried out in a tank reactor or a microchannel reactor. In some embodiments, the molar ratio of formaldehyde to another aldehyde is from 1:0.9 to 1: 1.05. In some embodiments, the aldol condensation reaction is carried out at a temperature of 60-130 degrees celsius, at a pressure of 1-5 MPa. In some embodiments, the methods of making hydroxyaldehydes described herein further comprise isolating the hydroxyaldehyde obtained.

Brief Description of Drawings

FIG. 1 shows a chromatogram of a gas phase analysis of the respective substances after the aldol condensation reaction is completed, when triethylamine is used as the first catalyst.

FIG. 2 shows a chromatogram of a gas phase analysis of the respective substances after the aldol condensation reaction is completed, when 270 resin is used as the first catalyst.

Detailed Description

While various aspects and embodiments will be disclosed below, it will be apparent to those skilled in the art that various equivalent changes and modifications can be made therein without departing from the spirit and scope of the subject matter of the present application. The various aspects and embodiments disclosed herein are presented by way of example only and are not intended to limit the present disclosure, which is to be controlled in the spirit and scope of the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. All references, patents, and patent applications cited in this application are hereby incorporated by reference in their entirety.

Process for the preparation of hydroxyaldehydes

In one aspect, the present application provides a method of preparing a hydroxyaldehyde comprising subjecting an aldehyde to an aldol condensation reaction in the presence of a first catalyst to obtain the hydroxyaldehyde, wherein at least one of the aldehydes is an aldehyde having an α -H, and the first catalyst is an immobilized catalyst comprising a solid support and a tertiary amine-based functional group.

In the present application, the term "hydroxyaldehyde" refers to an aldehyde bearing a hydroxyl group (-OH). In some embodiments, the hydroxyaldehyde bears one, two, three, four, five, or more hydroxyl groups. In some embodiments, the hydroxyaldehyde is selected from the group consisting of: dimethylolaldehyde, trimethylolacetaldehyde, 3-hydroxypropanal, 3-hydroxybutyraldehyde, 3-hydroxypentanal, 3-hydroxy-2-methylbutyraldehyde, 3-hydroxy-2-methylpentanal, 3-hydroxy-2-ethylhexanal, hydroxypivalaldehyde, and any combination thereof. In some embodiments, the hydroxyaldehyde is hydroxypivalaldehyde (also referred to as "HPA") having the formula:

in some embodiments, the aldehyde (e.g., the aldehyde in the reactants that undergo the aldol condensation reaction) comprises formaldehyde and another aldehyde. In some embodiments, the other aldehyde is an aldehyde having an α -H. "aldehyde having an α -H" refers to an aldehyde having a hydrogen atom on the carbon atom attached to the aldehyde group. In some embodiments, the other aldehyde is selected from the group consisting of: acetaldehyde, propionaldehyde, n-butyraldehyde, isobutyraldehyde, pivalaldehyde, isovaleraldehyde, hexanal, octanal, 2-methylbutyraldehyde, 2-methylvaleraldehyde, 3-methylvaleraldehyde, 4-methylvaleraldehyde, glutaraldehyde, and any combination thereof.

In some embodiments, the aldehyde in the reactants that undergo the aldol condensation reaction comprises or consists of formaldehyde and isobutyraldehyde. In some embodiments, the formaldehyde is used in the form of an aqueous solution. In some embodiments, the weight percentage of formaldehyde in the aqueous solution thereof is about 10 to 60 wt%, preferably about 15 to 55 wt%, about 20 to 50 wt%, about 25 to 45 wt%, about 30 to 40 wt%, or about 35 wt%, more preferably about 35 to 45 wt%, about 36 to 44 wt%, about 37 to 43 wt%, about 38 to 42 wt%, about 39 to 41 wt%, or about 40 wt%, and particularly preferably about 38 wt%.

Without being limited by theory, the main chemical reaction mechanism of formaldehyde and isobutyraldehyde in the present application under the action of the first catalyst is the classical Aldol condensation reaction, i.e. Aldol condensation or Aldol condensation reaction, to produce hydroxypivalaldehyde. In the reaction, isobutyraldehyde with alpha-H generates carbanion resonance hybrid under the action of a first catalyst, enolate is generated after the equilibrium is reached, and then the enolate is used as a nucleophilic reagent to carry out nucleophilic addition on formaldehyde to form a new carbon-carbon single bond to construct a hydroxypivalaldehyde product.

The aldol condensation reaction mechanism is illustrated below (taking the reaction of formaldehyde with isobutyraldehyde as an example):

in some embodiments, the solid support is used to immobilize a catalyst that catalyzes an aldol condensation reaction, but does not itself have a catalytic effect. In some embodiments, the solid support is capable of withstanding high temperatures, e.g., the refractory temperature of the solid support is higher than the reaction temperature of the aldol condensation reaction. For example, the solid support can withstand a temperature of 60 ℃ or higher, preferably 65 ℃ or higher, 70 ℃ or higher, 75 ℃ or higher, 80 ℃ or higher, 85 ℃ or higher, 90 ℃ or higher, 95 ℃ or higher, 100 ℃ or higher, 105 ℃ or higher, 110 ℃ or higher, 115 ℃ or higher, 120 ℃ or higher, 125 ℃ or higher, 130 ℃ or higher, and particularly preferably 130 ℃ or higher.

In some embodiments, the solid support is selected from the group consisting of: resins and inorganic or organic materials comprising carbon, silicon, transition metals or aluminum.

In some embodiments, the solid support is a resin. In the present application, the term "resin" refers to any of a number of physically similar polymeric compositions or chemically modified natural resins, including thermoplastics and thermosets, comprising polymer precursor compounds capable of giving a three-dimensional network structure in the presence of a suitable agent. The resin may be any polymer known to those skilled in the art to have chemical and thermal stability, for example, epoxy resins, phenolic resins, alkyd resins, nitrocellulose, amino resins, polyester resins, polyurethane resins, acrylic resins, polyarylethersulfone resins, silicone resins, and the like.

In some embodiments, the solid support is a photosensitive polyarylether, dimethylaminoethyl methacrylate-acrylonitrile copolymer, or polysulfone side-chain grafted poly-tertiary amine microfiltration membrane (PSF-g-PDMAEMA). Without being limited by theory, the glass transition temperature (Tg) of the resin should be higher than the reaction temperature of the aldol condensation reaction.

In some embodiments, the solid support is an inorganic or organic material comprising carbon, silicon or a transition metal or aluminum, for example, glass, ceramic, silica gel, diatomaceous earth, silica-alumina, magnesia, mixed support materials of palladium oxide and silica, solid supports composed of alumina and manganese oxide, Pd/C solid supports, MgO-CuO/Al₂O₃And the like. In some embodiments, the inorganic material comprising a transition metal is an inorganic material comprising, for example, copper, palladium, nickel, cobalt, rhodium, and platinum. In some embodiments, the transition metal-containing organic material is an aromatic-based organic material comprising, for example, copper, palladium, nickel, cobalt, rhodium, and platinum.

In some embodiments, the immobilized catalyst is selected from the group consisting of: photosensitive polyarylether containing tertiary amine functional groups on side chains, dimethylaminoethyl methacrylate-acrylonitrile copolymer and PSF-g-PDMAEMA. The structure of the above immobilized catalyst is shown in the following table:

The tertiary amine functionality can be attached to the solid support by routine procedures by those skilled in the art. In some embodiments, the tertiary amine functional group is covalently attached to the solid support. In some embodiments, the tertiary amine functional group is covalently attached to the solid support via a linker. In some embodiments, the linker is a photosensitive linker, a traceless linker, or an isolated cell linker. In some embodiments, the linker is an aromatic group (optionally, phenyl, naphthyl, anthracenyl), a saturated carbon chain, an ester chain, or a carbon ether chain, and the like.

In some embodiments, the tertiary amine-based functional group is non-covalently attached to the solid support, for example, by hydrogen bonding, electrostatic, van der waals forces, and the like. In some embodiments, the solid support is stretched to form microfibers, entangled with powdered catalytically active particles having tertiary amine-based functional groups into a porous material to form an immobilized catalyst.

In some embodiments, wherein the immobilized catalyst is selected from the group consisting of: 270 resin with N, N-dimethylanilinium groups attached, 607 resin with N, N-dimethylanilinium groups attached, Merrifield resin with ethylpiperazine attached.

In the present application, the functional groups attached to the solid support in the immobilized catalyst are tertiary amine functional groups, rather than primary, secondary, and quaternary amine functional groups. Without being limited by theory, the main reason for this may be that primary and secondary amine catalysts preferentially undergo an aldol condensation with an aldehyde (e.g., formaldehyde, isobutyraldehyde) as a reactant, resulting in failure to perform the intended aldol condensation reaction, and quaternary amine catalysts also result in failure to perform the intended aldol condensation reaction due to failure to abstract α -H of an aldehyde having α -H (e.g., isobutyraldehyde).

In some embodiments, the molar ratio of formaldehyde to another aldehyde as a reactant in the aldol condensation reaction is about 1:0.8 to about 1:1.2, preferably about 1:0.85 to about 1:1.15, about 1:0.9 to about 1:1.10, about 1:0.95 to about 1:1.05, or about 1:1 (or a range of values between any two of the above). In some embodiments, the molar ratio of formaldehyde to another aldehyde is about 1:0.95 or about 1: 1.05. In some embodiments, the molar ratio of formaldehyde to another aldehyde is about 1:1.

In some embodiments, the temperature of the aldol condensation reaction is about 30 to 120 degrees celsius, preferably about 35 to 115 degrees celsius, about 40 to 110 degrees celsius, about 45 to 105 degrees celsius, about 50 to 100 degrees celsius, about 55 to 95 degrees celsius, about 60 to 90 degrees celsius, about 65 to 85 degrees celsius, about 70 to 80 degrees celsius, or about 75 degrees celsius (or a range of values between any two of the above values), and more preferably about 70 to 75 degrees celsius.

In some embodiments, the reaction time of the aldol condensation reaction is about 0.5h to 4h, preferably about 0.6h to 3.9h, about 0.7h to 3.8h, about 0.8h to 3.7h, about 0.9h to 3.6h, about 1.0h to 3.5h, about 1.1h to 3.4h, about 1.2h to 3.3h, about 1.3h to 3.2h, about 1.4h to 3.1h, about 1.5h to 3.0h, about 1.6h to 2.9h, about 1.7h to 2.8h, about 1.8h to 2.7h, about 1.9h to 2.6h, about 2.0h to 2.5h, about 2.1h to 2.4h, or about 2.2h to 2.3h (or any number between any two of the above values, preferably about 1h to 3 h).

In some embodiments, the aldol condensation reaction is carried out in a tank reactor or microchannel reactor.

In some embodiments, the aldol condensation reaction is carried out in a tank reactor in the presence of an immobilized catalyst as described above. The filling mode of the immobilized catalyst in the tank reactor described in the application can be one or more of free, random and regular arrangement. The weight percent of the immobilized catalyst to the total reactants can be from about 10 wt% to about 60 wt%, preferably, from about 15 wt% to about 55 wt%, from about 20 wt% to about 50 wt%, from about 25 wt% to about 45 wt%, from about 30 wt% to about 40 wt%, or about 35 wt% (or a range of values between any two of the above), more preferably, from about 34 wt% or about 39 wt%. In some embodiments, the weight percentage of the immobilized catalyst to formaldehyde is about 50 wt% to about 200 wt%, preferably, about 60 wt% to about 190 wt%, about 70 wt% to about 180 wt%, about 80 wt% to about 170 wt%, about 90 wt% to about 160 wt%, about 100 wt% to about 150 wt%, about 110 wt% to about 140 wt%, about 120 wt% to about 139 wt%, about 138 wt%, about 137 wt%, about 136 wt%, about 135 wt%, about 134 wt%, about 133 wt%, about 132 wt%, about 131 wt%, about 130 wt%, more preferably, about 95.8 wt% or about 120 wt% (or a range of values between any two of the above).

In some embodiments, the aldol condensation reaction is performed in a tank reactor, the immobilized catalyst is about 35 wt% to about 40 wt% of the total reactants by weight, the formaldehyde is in a molar ratio to another aldehyde of about 1:0.95 to about 1:1.05, the temperature of the aldol condensation reaction is about 70-75 degrees celsius, and the reaction time is about 1 h-2 h.

In some embodiments, the aldol condensation reaction is performed in a tank reactor, the immobilized catalyst is about 30 wt% to about 45 wt% of the total reactants, the reactants of the aldol condensation reaction are formaldehyde and isobutyraldehyde, the molar ratio of formaldehyde to isobutyraldehyde is about 1:0.95 to about 1:1.05, the reaction temperature is about 70-75 degrees celsius, the reaction time is about 1 h-2 h, the immobilized catalyst is 270 resin having attached a tertiary amine group (e.g., N-dimethylaniline group) or 607 resin having attached a tertiary amine group (e.g., N-dimethylaniline group), and the hydroxyaldehyde is hydroxypivalaldehyde.

In some embodiments, the reaction is carried out in a microchannel reactor. In some embodiments, formaldehyde, which is one of the reactants of the aldol condensation reaction, is passed into the microchannel reactor at a rate of about 1.0ml/min to about 10.0ml/min, preferably about 1.5ml/min to about 9.5ml/min, about 2.0ml/min to about 9.0ml/min, about 2.5ml/min to about 8.5ml/min, about 3.0ml/min to about 8.0ml/min, about 3.5ml/min to about 7.5ml/min, about 4.0ml/min to about 7.0ml/min, about 4.1ml/min to about 6.5ml/min, about 4.2ml/min to about 6.0ml/min, about 4.3ml/min to about 5.5ml/min, about 4.4ml/min to about 5.4ml/min, about 4.5ml/min to about 5.5ml/min, about 4.4ml/min to about 5.5ml/min, about 4ml/min, about 4.5ml/min, about 5.5ml/min, about 4ml/min to about 5.5ml/min, about 5ml/min, about 5.5ml/min, about 4ml, About 4.8ml/min to about 5.0ml/min or about 4.9ml/min (or a range of values between any two of the above), and more preferably about 4.0 ml/min.

In some embodiments, another aldehyde that is one of the reactants of the aldol condensation reaction is passed into the microchannel reactor at a rate of about 1.0ml/min to about 10.0ml/min, preferably about 1.5ml/min to about 9.5ml/min, about 2.0ml/min to about 9.0ml/min, about 2.5ml/min to about 8.5ml/min, about 3.0ml/min to about 8.0ml/min, about 3.5ml/min to about 7.5ml/min, about 4.0ml/min to about 7.0ml/min, about 4.1ml/min to about 6.5ml/min, about 4.2ml/min to about 6.0ml/min, about 4.3ml/min to about 5.5ml/min, about 4.4ml/min to about 5.4ml/min, about 4.5ml/min to about 5.5ml/min, about 4ml/min to about 5.5ml/min, about 4ml/min, about 5.5ml/min, about 5ml/min, about 5.5ml/min, About 4.8ml/min to about 5.0ml/min or about 4.9ml/min (or a range of values between any two of the above), and more preferably about 4.3 ml/min.

In some embodiments, the total flow rate of formaldehyde and another aldehyde as reactants for the aldol condensation reaction into the microchannel reactor is about 2.0ml/min to about 20.0ml/min, e.g., about 3ml/min to about 19ml/min, about 4ml/min to about 18ml/min, about 5ml/min to about 17ml/min, about 6ml/min to about 16ml/min, about 7ml/min to about 15ml/min, about 8ml/min to about 14ml/min, about 9ml/min to about 13ml/min, about 10ml/min to about 12ml/min (or a range of values between any two of the above), preferably about 8ml/min to about 10ml/min, e.g., about 8.1ml/min, about 8.2ml/min, about 8.3ml/min, about 8.4ml/min, About 8.5ml/min, about 8.6ml/min, about 8.7ml/min, about 8.8ml/min, about 8.9ml/min, and the like.

In some embodiments, the reaction temperature of the aldol condensation reaction in the microchannel reactor is at least about 30 degrees celsius, preferably, at least about 30 degrees celsius, at least about 40 degrees celsius, at least about 50 degrees celsius, at least about 60 degrees celsius, at least about 70 degrees celsius, at least about 80 degrees celsius, at least about 90 degrees celsius, at least about 95 degrees celsius, at least about 100 degrees celsius, at least about 105 degrees celsius, at least about 110 degrees celsius, at least about 115 degrees celsius, at least about 120 degrees celsius, at least about 125 degrees celsius, at least about 130 degrees celsius, or at least about 135 degrees celsius (or a range of values between any two of the above values), and more preferably, at least about 130 degrees celsius.

In some embodiments, the reaction pressure of the aldol condensation reaction in the microchannel reactor is about 1 to 10MPa, preferably about 2 to 9MPa, about 3 to 8MPa, about 3.5 to 7.5MPa, about 4 to 7MPa, about 4.5 to 6.5MPa, about 5 to 6MPa, or about 5.5MPa, more preferably about 1 to 5MPa, about 1.5 to 4.5MPa, about 2 to 4MPa, about 2.5 to 3.5MPa (or a range of values between any two of the above values), or about 3 MPa. In some embodiments, the reaction pressure is 2 MPa.

In some embodiments, the aldol condensation reaction is conducted in a microchannel reactor, formaldehyde as one of the reactants of the aldol condensation reaction is passed into the microchannel reactor at a rate of about 4ml/min, another aldehyde as one of the reactants of the aldol condensation reaction is passed into the microchannel reactor at a rate of about 4.3ml/min, the reaction temperature of the aldol condensation reaction is at least 120 degrees celsius, and the reaction pressure is from about 1MPa to about 5 MPa.

In some embodiments, the aldol condensation reaction is performed in a microchannel reactor, the reactants of the aldol condensation reaction are formaldehyde and isobutyraldehyde, the total flow rate of formaldehyde and isobutyraldehyde into the microchannel reactor is about 8.3ml/min, the reaction temperature of the aldol condensation reaction is at least 120 degrees celsius (e.g., 120 degrees celsius to 150 degrees celsius), the reaction pressure is about 1 to 5MPa (e.g., 1, 2, 3, 4, 5MPa), the immobilized catalyst is 270 resin having attached tertiary amine groups (e.g., N-dimethylaniline groups) or 607 resin having attached tertiary amine groups (e.g., N-dimethylaniline groups), and the hydroxyaldehyde is hydroxypivalaldehyde.

In some embodiments, the aldol condensation reaction is carried out in a microchannel reactor, the reactants of the aldol condensation reaction are formaldehyde and isobutyraldehyde, the formaldehyde is passed into the microchannel reactor at a rate of about 4ml/min, the isobutyraldehyde is passed into the microchannel reactor at a rate of about 4.3ml/min, the aldol condensation reaction has a reaction temperature of at least 120 degrees celsius (e.g., 120 degrees celsius to 150 degrees celsius), a reaction pressure of about 1 to 5MPa (e.g., 1, 2, 3, 4, 5MPa), the immobilized catalyst is 270 resin having attached tertiary amine groups (e.g., N-dimethylanilinium groups) or 607 resin having attached tertiary amine groups (e.g., N-dimethylanilinium groups), and the hydroxyaldehyde is hydroxypivalaldehyde.

In some embodiments, the microchannel reactor used in the present application comprises 10 to 20 microchannel reaction columns, preferably 11 to 19 microchannel reaction columns, 12 to 18 microchannel reaction columns, 13 to 17 microchannel reaction columns, 14 to 16 microchannel reaction columns, or 15 microchannel reaction columns, more preferably 12 microchannel reaction columns.

The method for preparing hydroxyaldehyde described in the present application optionally further comprises cleaning and regenerating the immobilized catalyst while the aldol condensation reaction is performed. Without being limited by theory, it is possible that the pH of the system changes due to formic acid and some other acids generated during the aldol condensation reaction, beyond the catalytically active pH range of the immobilized catalyst used (e.g., tertiary amine functionalized resin catalyst), resulting in the possibility of gradual deactivation and decay of the immobilized catalyst used. Therefore, the immobilized catalyst is cleaned while the aldol condensation reaction is catalyzed, so that the service life of the catalyst can be prolonged, the time is saved, and the production efficiency is obviously improved.

The plurality of microchannel reaction columns in the microchannel reactor can be connected in series or in parallel. The washing and regeneration of the immobilized catalyst while the aldol condensation reaction is in progress can be accomplished by one skilled in the art in a variety of ways. In the reaction process, the states of the micro-channel reaction columns can be switched by computer control or manual control. For example, when the catalytic activity of the catalyst in a microchannel reaction column is reduced or deactivated, the microchannel reaction column may be switched to an alkaline washing state for regeneration, and then switched to a water washing state after the alkaline washing is finished, and then switched to a reaction state after the water washing is finished. A plurality of microchannel reaction columns in the microchannel reactor form a system of reaction, regeneration and re-reaction in such a way, so that the reaction can be continuously produced without interruption, thereby greatly improving the reaction efficiency.

The medium for washing the immobilized catalyst by the skilled person may be any medium capable of bringing the immobilized catalyst to a pH value within its catalytic activity range, which medium may be liquid, such as clear water or solutions of inorganic bases, including alkali and alkaline earth metal carbonate, bicarbonate and hydroxide solutions, such as Na₂CO₃、K₂CO₃、NaHCO₃、KHCO₃NaOH, KOH, and Ca (OH)₂And (3) solution. The above inorganic base solution is preferably used as an aqueous solution, for example, in a concentrated concentration of about 5 wt% to about 50 wt%And (4) using the Chinese medicinal composition.

The method for preparing hydroxyaldehydes comprising a wash regeneration step can repeat using the immobilized catalyst at least 3 times, preferably, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 11 times, at least 12 times, at least 13 times, at least 14 times, at least 15 times, at least 16 times, at least 17 times, at least 18 times, at least 19 times, at least 20 times, at least 21 times, at least 22 times, at least 23 times, at least 24 times, at least 25 times, or more.

In some embodiments, the methods of making hydroxyaldehydes described herein optionally further comprise isolating the hydroxyaldehyde obtained. The separation may be carried out by any separation method known to those skilled in the art, such as rectification separation, distillation separation, filtration separation, and the like.

In some embodiments, the hydroxyaldehydes prepared according to the methods described herein can be subjected to subsequent reactions without isolation. In some embodiments, the hydroxyaldehydes prepared according to the methods described herein are substantially free of immobilized catalyst and/or other impurities. For example, hydroxyaldehydes prepared by the methods described herein have a purity of greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 99%, or even 100%.

Process for producing polyhydroxy alcohol compound

In another aspect, the present application also provides a method of making a polyhydroxy alcohol compound. In some embodiments, the method comprises: (a) subjecting aldehydes to an aldol condensation reaction in the presence of a first catalyst to obtain hydroxyaldehydes, wherein at least one of the aldehydes is an aldehyde having an alpha-H, the first catalyst being an immobilized catalyst comprising a solid support and a tertiary amine-based functional group; (b) hydrogenating the hydroxyaldehyde obtained in step (a) to form a polyhydroxyl alcohol compound.

Step (b) (i.e., the hydrogenation step or the reduction step) can be performed by one skilled in the art according to conventional procedures in the art. For example, hydroxyaldehydes (e.g., HPA) can be converted to polyhydroxyl compounds (e.g., neopentyl glycol) as intermediates by Cannizzaro (Cannizzaro) reaction with excess formaldehyde.

It is also commercially possible to catalytically hydrogenate hydroxyaldehydes (e.g., HPAs) in the vapor and liquid phases with metal catalysts, such as hydrogenation catalysts containing nickel, cobalt, copper, or lanthanum.

For example, in the gas phase modification, the hydroxyaldehyde (e.g., HPA) prepared in step (a) is first isolated and then catalytically hydrogenated with a metal catalyst, which may additionally comprise activators for other active metals (e.g., copper, chromium), wherein the gas phase modification is described in, for example, EP0278106A1, US4094914, Ullmann's Encyclopedia of Industrial Chemistry, publisher VCH,5th Ed.,1985, Vol. Al, p.308, Chemiker-Zeitung (Chemicaljoural), volume 100, (1976), No.12, pp.504-514.

Also for example, the hydroxyaldehydes (e.g., HPAs) prepared in step (a) may also be hydrogenated in the liquid phase using a catalyst based on copper, zinc and zirconium, see in particular EP0484800a 2. Wherein when the hydroxyaldehyde is hydroxypivalaldehyde, the liquid phase hydrogenation thereof may be carried out in the presence of a copper chromite catalyst which also contains other metals as activators, such as barium, cadmium, magnesium, manganese and/or rare earth metals, as described in particular in US4855515, a manganese doped copper chromite catalyst being used in the hydrogenation of the aldol condensation product of the reaction of formaldehyde with isobutyraldehyde, WO98/29374a1 discloses the use of a barium doped copper chromite for the hydrogenation of hydroxypivalaldehyde in a methanol solution.

In some embodiments, the hydroxyaldehyde (e.g., HPA) produced in step (a) is directly subjected to the hydrogenation step without any additional separation step. The hydrogenation step may be carried out in a solvent, for example, water, alcohols, ketones and ethers solvents, such as methanol, ethanol, propanol, isobutanol, hexanol, octanol, neopentyl glycol, butyl ether or dioxane. The amount of solvent may vary from 1 to 70 wt%.

The hydrogenation step may be carried out under conditions of elevated temperature and pressure. For example, the temperature can be between 50 and 200 degrees Celsius (e.g., 70 and 120 degrees Celsius), and the pressure can be between 1 and 6MPa (e.g., 1MPa, 2MPa, 3MPa, 4MPa, 5MPa, 6 MPa). The hydrogenation step may be carried out in a batch or semi-batch process, or in a continuous process.

In some embodiments, the reaction time of the hydrogenation step is about 1h to 6h, for example, about 1h, 2h, 3h, 4h, 5h, 6h (or a range of values between any two of the above), and particularly preferably about 3h to 4 h.

In some embodiments, in the method for preparing a polyhydric alcohol compound described herein, Raney Ni is used as a catalyst in the step (b), and the reaction is carried out at a temperature of 100 to 120 ℃ and a pressure of 3 to 4MPa for 3 to 4 hours.

In some embodiments, the polyol compound prepared by the methods described herein is neopentyl glycol. In some embodiments, the aldehyde that is a reactant in the aldol condensation reaction in step (a) comprises or consists of formaldehyde and isobutyraldehyde.

In some embodiments, after the hydrogenation step, the resulting polyol compound produced is separated from the reaction mixture by a suitable method (e.g., distillation), and the solvent may be recovered for reuse in the hydrogenation and/or aldol condensation reaction steps.

Process for preparing polyhydroxy acid compounds

In another aspect, the present application also provides a method of preparing a polyhydroxy acid compound. In some embodiments, the method comprises: (a) subjecting aldehydes to an aldol condensation reaction in the presence of a first catalyst to obtain hydroxyaldehydes, wherein at least one of the aldehydes is an aldehyde having an alpha-H, the first catalyst being an immobilized catalyst comprising a solid support and a tertiary amine-based functional group; (b) oxidizing the hydroxyaldehyde obtained in step (a) to form a polyhydroxy acid compound.

Step (b) (i.e., the oxidation step) can be performed by one skilled in the art according to conventional procedures in the art. For example, the hydroxy aldehyde prepared in step (a) is reacted with a carboxylic acid to protect the hydroxyl group, and then oxidized with potassium permanganate and hydrolyzed to obtain the polyhydroxy acid compound. Or, for example, oxidizing the hydroxyaldehyde prepared in step (a) to the polyhydroxy acid compound in an alkaline solution (e.g., sodium hydroxide solution) using a mixture of different metal oxides (e.g., a mixture of bismuth oxide and aluminum oxide) as a catalyst.

For another example, polyhydroxy acid compounds are prepared by bromine oxidation. For example, liquid bromine is added to the hydroxyaldehyde prepared in step (a), the temperature is raised to 40-60 ℃ (for example, 50 ℃) to react for 1-3 hours (for example, 2 hours), the excess liquid bromine aqueous solution is recovered by reduced pressure distillation, the pH of the residue is adjusted to be alkaline (for example, pH 10) by an alkaline solution (for example, sodium hydroxide solution), impurities and unreacted hydroxyaldehyde are extracted by toluene, the pH of the aqueous phase is adjusted to be acidic (for example, pH 2) by an acidic solution (for example, hydrochloric acid), the aqueous phase is extracted by toluene, the organic phase is partially desolventized and then slowly crystallized by cooling, and the polyhydroxy acid compound is obtained.

For another example, polyhydroxy acid compounds are prepared by electrooxidation. For example, the hydroxyaldehyde prepared in step (a) is placed at an anode of an electrolytic cell, after reaction for 1-2 hours, the pH is adjusted to be alkaline (for example, pH 10) by an alkaline solution (for example, sodium hydroxide solution), toluene is used for extracting impurities and unreacted hydroxyaldehyde, the pH of an aqueous phase is adjusted to be acidic (for example, pH 2) by an acidic solution (for example, hydrochloric acid), toluene is used for extraction, an organic phase is partially desolventized, and then temperature is reduced to slowly crystallize, so that the polyhydroxy acid compound is obtained. In some embodiments, the electrolytic cell has an anode of PbO2/Ti, a cathode of aqueous sulfuric acid/sodium sulfate solution with pH 2, a cathode of Pt, and a diaphragm, wherein the electrolyte is 0.05mol/L sulfuric acid solution.

In some embodiments, in step (b) of the method for preparing a polyhydroxy acid compound, liquid bromine is used as an oxidizing agent, and the pH value is adjusted to 1-2, and the method is carried out in an aqueous phase under normal pressure conditions.

In some embodiments, the polyhydroxy acid compound prepared by the methods described herein is hydroxypentanoic acid. In some embodiments, the aldehyde that is a reactant in the aldol condensation reaction in step (a) comprises or consists of formaldehyde and isobutyraldehyde.

Method for resolving optical isomers using electrodialysis techniques

In another aspect, the present application provides a novel method for resolving optical isomers. The method can make up the defects of the existing chiral resolution process, and replaces the traditional organic solvent extraction process with electrodialysis technology by utilizing different ionization degrees of optical isomers in the chiral resolution product, thereby improving the yield and the quality of the product and reducing the production cost.

The present application provides a method for resolving optical isomers from racemates by electrodialysis, comprising:

In the method, because the immobilized catalyst is used, the hydroxyaldehyde prepared in the step (a) can enter the step (b) to prepare the lactone racemate without further purification or separation, so that the production cost is reduced. In certain embodiments, the cyanide in step (b) is cyanohydric acid, sodium cyanide, or potassium cyanide. The acidic condition in step (b) may be an inorganic acid such as hydrochloric acid, sulfuric acid or nitric acid, or an organic acid having a carboxyl group (e.g., tartaric acid, oxalic acid, malic acid, citric acid, benzoic acid, etc.). In step (b), the hydroxyaldehyde obtained in step (a) is reacted with cyanide under acidic conditions to form a lactone racemate through cyanation, hydrolysis, cyclization and the like. For example, in certain embodiments, a cyanide (e.g., cyanohydric acid or sodium cyanide) attacks the aldehyde group of the hydroxy aldehyde prepared in step (a) under acidic conditions (e.g., sulfuric acid), undergoes an addition reaction, is subsequently heated to hydrolyze the cyano group to the acid, and then forms a lactone racemate with the intramolecular hydroxyl ring.

In the present application, "racemic body" means a mixture having two or more optical isomers with different optical rotation properties. For example, a compound having one chiral center may have two optical isomers, one having a chiral center of the R configuration and the other having a chiral center of the S configuration. For this compound, the racemate includes both an optical isomer in the R configuration and an optical isomer in the S configuration. In the racemates described herein, the different optical isomers may be present in equal molar amounts (i.e., optical rotation offsets) or may be present in unequal molar amounts.

In certain embodiments, the racemate has hydrolyzable functionality. Hydrolyzable functional groups such as, but not limited to, ester linkages, amide linkages, and the like. In certain embodiments, the functional group can be hydrolyzed to form an ionizable group. Ionizable groups refer to groups that ionize in aqueous solution, e.g., carboxyl, amino, and the like. Ionizable groups, upon ionization, produce charged groups such as negatively charged carboxylates, positively charged ammonia ions, and the like. In certain embodiments, the chiral center in the racemate may be located in or near the hydrolyzable functional group, for example on an atom adjacent to the hydrolyzable functional group, or at a position spaced 1, 2 or 3 atoms from it.

In the methods of the present application, the second catalyst can specifically react with (e.g., hydrolyze a hydrolyzable functional group in) a particular optical isomer in the racemate to render it in an ionizable form. By "ionizable form" is meant herein that it ionizes to form charged groups in aqueous solution. In certain embodiments, the ionizable form can comprise an ionizable group, such as a carboxyl group, an amino group, and the like. In certain embodiments, the second catalyst may not catalyze the second optical isomer in the racemate, leaving it in its non-ionized form. By "non-ionized form" is meant herein that it does not ionize in aqueous solution, nor has charged groups. In certain embodiments, the non-ionized form comprises a non-ionized group, such as an ester (e.g., a lactone in a racemate), an amide, an ether, and the like.

In certain embodiments, the racemate has a ring structure, and the hydrolyzable functional group may be in the ring structure. Exemplary ring structures are, for example, lactones. These intra-ring functional groups can react to open the ring. In certain embodiments, the ring structure is closed-loop in the non-ionized form of the second optical isomer. In certain embodiments, the ring structure is open-looped in the ionizable form of the first optical isomer. For example, when a ring-opening reaction occurs with an intra-ring functional group, an ionizable group is formed. Or in certain embodiments, the ring structure is open in the non-ionized form of the second optical isomer, and/or closed in the ionizable form of the first optical isomer. In a racemate having a ring structure, the chiral center may or may not be present at a ring atom.

In certain embodiments, the racemate is a lactone. The lactone means that it has an intramolecular ester bond (-C (O) formed by dehydration of a carboxyl group and a hydroxyl group in its molecular structure. Usually the intramolecular ester bond is in a ring structure. Examples of lactones are, for example, DL racemohydropantoic acid lactone, β -butyrolactone, γ -butyrolactone, α -hydroxy- γ -butyrolactone, β -hydroxy- γ -butyrolactone, α -acetyl- γ -butyrolactone, n-butylphthalide and the like.

In certain embodiments, the second catalyst comprises an enzyme composition. In certain embodiments, the enzyme composition comprises an enzyme that is capable of specifically reacting with an optical isomer. For example, specifically with the D-configuration optical isomer, or specifically with the L-configuration optical isomer. In certain embodiments, the enzyme composition comprises an ester hydrolase. In certain embodiments, the ester hydrolase specifically catalyzes the D-configuration of a lactone. Exemplary ester hydrolyzing enzymes include, for example, D-pantolactone hydrolase, Novozyme 435 lipase, beta-butyrolactone hydrolase, gamma-butyrolactone hydrolase, alpha-hydroxy-gamma-butyrolactone hydrolase, beta-hydroxy-gamma-butyrolactone hydrolase, alpha-acetyl-gamma-butyrolactone hydrolase, n-butylphthalide hydrolase, and the like. Taking D-pantoic acid lactone hydrolase as an example, the hydrolase can specifically hydrolyze D-configuration pantoic acid lactone in a racemate, so that lactone structures in the D-configuration pantoic acid lactone are hydrolyzed to form intramolecular independent carboxyl and hydroxyl, wherein the carboxyl can be ionized in aqueous solution and can be charged and can be in an ionizable form. However, the D-pantoic acid lactone hydrolase can not hydrolyze L-configuration pantoic acid lactone in a racemate, so that the L-configuration pantoic acid lactone still keeps a lactone structure in a non-ionized form after catalytic reaction. As another example, Novozyme 435 lipase can specifically hydrolyze R-configured methyl 3-cyclohexene-1-carboxylate in the racemate to form 3-cyclohexene-1-carboxylate, which is ionizable in aqueous solutions. Methyl 3-cyclohexene-1-carboxylate in the S-configuration remains in its non-ionised form since it cannot be hydrolysed.

In certain embodiments, the enzyme composition comprises a lactamase. In certain embodiments, the lactamase specifically catalyzes a D-configuration lactam. Exemplary lactamases are, for example, beta-lactamases, gamma-lactamases. Taking beta-lactamase as an example, the beta-lactamase can specifically hydrolyze D-configuration beta-lactam in a racemate, so that the lactam structure in the beta-lactam is hydrolyzed to form intramolecular independent carboxyl and amino, wherein the carboxyl can be ionized in aqueous solution and can be charged and can be in an ionizable form. However, the beta-lactamase can not hydrolyze the L-configuration beta-lactam in the racemate, so the L-configuration beta-lactam still maintains the lactam structure after the catalytic reaction and is in a non-ionized form.

In certain embodiments, the racemate described herein is DL-pantoic acid lactone, the first optical isomer is D-pantoic acid lactone, the second optical isomer is L-pantoic acid lactone, the ionizable form of the first optical isomer is D-pantoic acid, and the nonionized form of the second optical isomer is L-pantoic acid lactone.

Any form of enzyme having a selective catalytic function for optical isomers may be used. In certain embodiments, the enzyme composition may contain a purified enzyme, a cell expressing an enzyme, or a lysate of a cell expressing an enzyme. The cell expressing the enzyme may be any suitable host cell, either prokaryotic, such as bacteria, or eukaryotic, such as yeast, animal cells, and the like. The cell lysate can be any component of a lysate containing an enzyme, such as a cell lysate or the like. In certain embodiments, the enzyme composition is immobilized on a substrate. Suitable substrates may include materials for immobilized enzymes, such as magnetic particles, macroporous resins, and the like; materials for immobilizing the cells, such as calcium alginate, gels, and the like, may also be included.

In certain embodiments, the step (c) maintains the pH during the reaction in the range of 7.0 to 7.5, for example, the pH is maintained at 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, or any value between any two of the above numerical ranges. In certain embodiments, 15N NH is used₃·H₂O-titration maintained the pH. In certain embodiments, the temperature of step (c) during the reaction is maintained between 20 ℃ and 40 ℃, e.g., 20 ℃, 21 ℃, 22 ℃, 23 ℃, 24 ℃, 25 ℃, 26 ℃, 27 ℃, 28 ℃, 29 ℃, 30 ℃, 31 ℃, 32 ℃, 33 ℃, 34 ℃, 35 ℃, 36 ℃, 37 ℃, 38 ℃, 39 ℃, 40 ℃ or any value between any two of the above numerical ranges. In certain embodiments, the reaction time of step (c) is 1 to 10 hours, such as 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, or any value between any two of the above numerical ranges.

In certain embodiments, after step (c) and before step (d), further comprising: removing the residue of the second catalyst in the mixture. The residue includes cell debris, proteins and other macromolecules, and the skilled person can remove the residue of the second catalyst in the mixture by using conventional separation means according to the actual needs of the skilled person, for example, one or more of various means such as filtration, centrifugation, microfiltration, ultrafiltration and the like.

In certain embodiments, the filtration is achieved by using filter paper or filter cloth. The filter paper or filter cloth described herein may be a commercially available filter paper or filter cloth, such as those manufactured by GE Healthcare Life Sciences, Shibi pure, Asahi Chemicals, and the like. In certain embodiments, the filter paper or filter cloth has a pore size of 10 to 150 μm, such as 10 μm, 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm, 110 μm, 120 μm, 130 μm, 140 μm, 150 μm, or any number between any two of the above numerical ranges. One skilled in the art can select a suitable filter paper or filter cloth pore size to remove the residue of the second catalyst according to the type and size of the residue of the second catalyst.

In certain embodiments, the centrifugation is achieved by using a centrifugal separator. The centrifugal separator described in this application may be a commercially available centrifugal separator such as those manufactured by Guangzhou Fuyi liquid separation technology, Inc., cigarette counter Chengbo mechanical technology, Inc., Yao electric technology, Inc. of Dongguan, TEMA System, Kyte, Heinkel, GEA, etc. In certain embodiments, the centrifugation rate is 1000rpm to 2000rpm, such as 1000rpm, 1100rpm, 1200rpm, 1300rpm, 1400rpm, 1500rpm, 1600rpm, 1700rpm, 1800rpm, 1900rpm, 2000rpm, or any value between any two of the above numerical ranges. In certain embodiments, the centrifugation time is 2 to 15 minutes, e.g., 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 11 minutes, 12 minutes, 13 minutes, 14 minutes, 15 minutes, or any value between any two of the above numerical ranges. One skilled in the art can select a proper centrifugation speed and centrifugation time to remove the residue of the second catalyst according to the kind and size of the residue of the second catalyst.

In certain embodiments, the microfiltration is achieved by passing the mixture through a microfiltration membrane. The microfiltration membrane described in the present application may be a commercially available microfiltration membrane, such as a microfiltration hollow fiber membrane series produced by GE Healthcare Life Sciences, Shibi pure, Asahi chemical company, and the like. In certain embodiments, the pore size of the microfiltration membrane is between 0.1 μm and 0.6 μm, such as 0.1 μm, 0.15 μm, 0.2 μm, 0.22 μm, 0.25 μm, 0.3 μm, 0.35 μm, 0.4 μm, 0.45 μm, 0.5 μm, 0.55 μm, 0.6 μm, or any value between any two of the above numerical ranges. Depending on the size of the residue of the second catalyst, the selection of a microfiltration membrane pore size as small as possible facilitates the removal of large particle residues.

In certain embodiments, the ultrafiltration is achieved by passing the mixture through an ultrafiltration membrane. The ultrafiltration membrane described in the present application may be a commercially available ultrafiltration membrane, such as a series of ultrafiltration hollow fiber membranes manufactured by GE Healthcare Life Sciences, Shibi pure, Asahi chemical Co. In certain embodiments, the ultrafiltration membrane is a hollow fiber ultrafiltration membrane having a pore size of from 10kD to 500kD, such as a hollow fiber ultrafiltration membrane having a pore size of 10kD, 20kD, 30kD, 40kD, 50kD, 60kD, 70kD, 80kD, 90kD, 100kD, 150kD, 200kD, 250kD, 300kD, 350kD, 400kD, 450kD, 500kD, or any value in between any two of the above numerical ranges. One skilled in the art can select a suitable ultrafiltration membrane pore size to remove the residue of the second catalyst according to the size of the residue of the second catalyst.

In certain embodiments, the methods of resolving optical isomers described herein further comprise purifying and/or concentrating the ionizable form of the isolated first optical isomer, and/or purifying and/or concentrating the nonionized form of the isolated second optical isomer.

In certain embodiments, the isolated ionizable form of the first optical isomer and/or the non-ionizable form of the second optical isomer can be further purified. For example, the ionizable form of the first optical isomer and/or the non-ionizable form of the second optical isomer can be extracted by using a suitable solvent. For example, an organic solvent (e.g., ethyl acetate) may be added to the collected (R) -3-cyclohexene-1-carboxylic acid, and the organic phase may be collected to obtain purified (R) -3-cyclohexene-1-carboxylic acid. For another example, an organic solvent (e.g., ethyl acetate) may be further added to the collected methyl (S) -3-cyclohexene-1-carboxylate, and the organic phase may be collected to obtain a purified methyl (S) -3-cyclohexene-1-carboxylate.

In certain embodiments, the isolated and/or purified ionizable form of the first optical isomer and/or the non-ionized form of the second optical isomer can be further concentrated. In certain embodiments, the concentration is achieved by reduced pressure, e.g., the isolated and/or purified ionizable form of the first optical isomer and/or the isolated and/or purified nonionized form of the second optical isomer is pumped to a concentration device for concentration under reduced pressure.

In certain embodiments, the present application further comprises converting the non-ionized form of the second optical isomer into the racemate. The non-ionized form of the second optical isomer may have been isolated by the methods provided herein, or further purified, or further concentrated. For example, when the racemate is an ester, the non-ionized form of the second optical isomer that is separated (i.e., the ester) can be racemized to give a racemate having a different chiral isomer. By reconverting the resolved second optical isomer to the racemate, it may allow further chiral resolution by the methods provided herein to obtain more of the first optical isomer.

In certain embodiments, the present application further comprises converting the ionizable form of the separated first optical isomer into a non-ionizable form. In certain embodiments, the ionizable form of the isolated (and/or purified or concentrated) first optical isomer can be further reacted to restore the ionizable groups thereof to hydrolyzable functionality. For example, in certain embodiments, the ionizable form of the isolated first optical isomer is D-pantoic acid, which can be lactonized to yield D-pantoic lactone, thereby restoring the ionizable group (i.e., carboxyl group) therein to a hydrolyzable functionality (i.e., lactone).

The electrodialysis step in the process of the present application can be carried out by a person skilled in the art using known methods and equipment. The device and method for electrodialysis are described in the "industry Standard of the people's republic of China-electrodialysis technology HY/T034.1-034.5-1994".

In certain embodiments, the electrodialysis treatment is performed in an electrodialysis cell having a depleting compartment and a concentrating compartment separated by an ion exchange membrane. In certain embodiments, the ion exchange membrane is a homogeneous membrane or a heterogeneous membrane. During the electrodialysis process, anions and cations migrate toward the anode and cathode, respectively, under the drive of an applied electric field, using the permselectivity of the ion exchange membrane (e.g., cations can permeate through the cation exchange membrane and anions can permeate through the anion exchange membrane).

A variety of ion exchange membranes known in the art can be selected by those skilled in the art to perform electrodialysis, depending on their practical needs. In certain embodiments, the ion exchange membrane is an anion exchange membrane, such as a Q membrane. In certain embodiments, the ion exchange membrane is a cation exchange membrane, such as an S-membrane. In certain embodiments, the ion exchange membranes are cation exchange membranes and anion exchange membranes. In certain embodiments, the cation exchange membrane allows cations to pass through while repelling blocking anions. In certain embodiments, the anion exchange membrane allows anions to pass through while repelling blocks cations from passing through. In some embodiments, the compartments formed between the cation exchange membrane and the anode and between the anion exchange membrane and the cathode are concentrating compartments, and the compartments formed between the cation membrane and the anion membrane are depleting compartments. In certain embodiments, the cation exchange membranes and anion exchange membranes are commercially available, for example, from Novasep, Eurodia, shandongtianwei membrane technologies, ltd, seiku water treatment, and the like.

In certain embodiments, the skilled person may select the membrane stack size of the homogeneous or heterogeneous membrane according to their actual needs, e.g. 10 x 20cm, 10 x 30cm, 20 x 30cm, etc. In certain embodiments, the number of membrane pairs of the homogeneous or heterogeneous membranes can be selected by one skilled in the art according to their actual needs, e.g., 5 pairs, 10 pairs, 15 pairs, 20 pairs, etc.

In certain embodiments, the electrodialysis process comprises placing the mixture in the depletion compartment and a solvent in the concentration compartment, and energizing the electrodialysis cell such that the ionizable form of the first optical isomer in the depletion compartment migrates into the solvent in the concentration compartment.

In some embodiments, the flow rate is adjusted during the electrodialysis treatment to adjust the pressure in the concentration compartment and the desalination compartment such that the pressure in the concentration compartment is 1 time, 2 times, 3 times, 4 times, 5 times or any value between any two of the above numerical ranges. In certain embodiments, the electrodialysis treatment is performed at a constant voltage until the conductivity of the depleting compartments is less than 30 μ s/cm, 40 μ s/cm, 50 μ s/cm, 60 μ s/cm, 70 μ s/cm, 80 μ s/cm, 90 μ s/cm, 100 μ s/cm, 110 μ s/cm, 120 μ s/cm, 130 μ s/cm, 140 μ s/cm, 150 μ s/cm, and the like. In certain embodiments, the constant voltage is 10V, 15V, 20V, 25V, 30V, 35V, 40V, 45V, 50V, or the like.

In certain embodiments, the solvent comprises pure water.

In certain embodiments, the electrodialysis treatment is performed in one electrodialysis cell. In certain embodiments, step (d) of the method of resolving optical isomers described herein may be repeated in the electrodialysis cell to increase the separation efficiency. For example, the concentrated compartment liquor may be pumped cyclically into a depletion compartment of an electrodialysis cell in the electrodialysis unit to repeat the electrodialysis step in the electrodialysis cell.

In certain embodiments, the electrodialysis treatment is performed in more than one electrodialysis cell in series. For example, the concentrate compartment supernatant is pumped into the desalination compartments of a two-, three-, four-, or even more-stage electrodialysis device, and step (d) of the method described herein is repeated, thereby increasing the separation efficiency. In some embodiments, the pressure in the concentrating compartments and the pressure in the desalting compartments are the same between different electrodialysis cells. In some embodiments, the pressure in the concentrating compartments and the pressure in the desalting compartments differ between different electrodialysis cells. In some embodiments, the voltage between the different electrodialysis cells is the same. In some embodiments, the voltage is different between different electrodialysis cells.

The optical isomers resolved using the methods of the present application have a purity of greater than 90%, e.g., greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 99%, or even 100%. In certain embodiments, the purity of the optical isomers resolved using the methods of the present application is expressed in terms of ee, which can be measured or calculated by one of skill in the art according to conventional techniques in the art (e.g., HPLC methods), e.g., where a racemate contains A, B two optical isomers, the ee is between a% and B%.

Compared with the prior art, the method has at least the following advantages:

1. the application provides a high-efficiency, economical and environment-friendly synthesis process of hydroxyaldehyde (such as HPA), which comprises the steps of replacing organic or inorganic base in the traditional process with an immobilized catalyst as a catalyst, wherein the catalyst used for catalyzing aldol condensation reaction has low regeneration cost and can be repeatedly used, so that the production cost is reduced;

2. the catalytic effect of the immobilized catalyst used in the method is equivalent to that of the catalyst used in the prior art, and the two defects that the catalyst in the prior art cannot be separated from a product (namely, hydroxyaldehyde) and is not environment-friendly are overcome, so that the purity of the obtained product is higher, and the emission of dangerous wastes is reduced;

3. the method can be used for cleaning and regenerating the immobilized catalyst in the process of preparing the hydroxyaldehyde, and can effectively maintain the activity of the immobilized catalyst so that the immobilized catalyst can be repeatedly used, thereby reducing the production cost of the hydroxyaldehyde, improving the product yield and improving the production efficiency;

4. the method optimizes various reaction conditions in the preparation process of the hydroxyaldehyde, the polyhydroxy alcohol compound and the polyhydroxy acid compound, such as the molar ratio of reactants (such as formaldehyde and isobutyraldehyde), reaction temperature, reaction pressure, the type and the dosage of a catalyst and the like, and explores a preferable preparation process for preparing the hydroxyaldehyde (such as hydroxypivalaldehyde), the polyhydroxy alcohol compound and the polyhydroxy acid compound, so that the product yield is improved, and the operation steps are simplified;

5. the application combines a biological catalysis (for example, enzyme catalysis) technology with an electrodialysis technology, utilizes different ionization degrees of products generated by enzyme catalysis, and uses the electrodialysis technology to split optical isomers in racemes, so that the reaction condition is mild, and the operation steps are reduced;

6. the electrodialysis technology replaces the conventional extraction means such as the traditional organic solvent extraction, the use amount of the organic solvent is greatly reduced, the production cost is reduced, and the environmental pollution is reduced;

7. the method improves the extraction rate of the product, has good product purity, can be directly applied, does not need further refining, reduces the working procedures and has more cost advantage;

8. the application process is simple and easy to implement, is convenient for automatic operation, improves the operation safety index, and improves the working environment of workers.

The present application provides the following embodiments:

embodiment 1: a method of resolving optical isomers from racemates by electrodialysis, comprising:

subjecting aldehydes to an aldol condensation reaction in the presence of a first catalyst to obtain hydroxyaldehydes, wherein at least one of the aldehydes is an aldehyde having an alpha-H, the first catalyst being an immobilized catalyst comprising a solid support and a tertiary amine-based functional group;

reacting the hydroxyaldehyde obtained in the step (a) with cyanide under an acidic condition to form a lactone racemate;

reacting the lactone racemate obtained in step (b) in the presence of a second catalyst to form a mixture comprising an ionizable form of the first optical isomer and a non-ionizable form of the second optical isomer;

subjecting the mixture obtained in step (c) to an electrodialysis treatment to allow the ionizable form of the first optical isomer and the non-ionizable form of the second optical isomer to be separated; and

collecting the separated ionizable form of the first optical isomer, and/or collecting the separated nonionized form of the second optical isomer.

Embodiment 2: the method of embodiment 1, wherein the second catalyst comprises an enzyme composition.

Embodiment 3: the method of embodiment 2, wherein the enzyme composition comprises an ester hydrolase.

Embodiment 4: the method of embodiment 2 or 3, wherein the enzyme composition comprises a purified enzyme, a cell expressing an enzyme, or a lysate of a cell expressing an enzyme.

Embodiment 5: the method of any of embodiments 2-4, wherein the enzyme composition is immobilized on a substrate.

Embodiment 6: the method of any of embodiments 1-5, further comprising after step (c) and before step (d): removing the residue of the second catalyst in the mixture.

Embodiment 7: the method of any one of embodiments 1-6, further comprising purifying and/or concentrating the isolated ionizable form of the first optical isomer, and/or purifying and/or concentrating the isolated nonionized form of the second optical isomer.

Embodiment 8: the method of any one of embodiments 1-7, further comprising converting the non-ionized form of the second optical isomer into the racemate.

Embodiment 9: a method as in any of embodiments 1-8 wherein the electrodialysis treatment is performed in an electrodialysis cell having a depleting compartment and a concentrating compartment separated by an ion exchange membrane.

Embodiment 10: the method of embodiment 9, wherein the electrodialysis treatment comprises placing the mixture in the depletion compartment and a solvent in the concentration compartment, and energizing the electrodialysis cell causes the ionizable form of the first optical isomer in the depletion compartment to migrate into the solvent in the concentration compartment.

Embodiment 11: the method of embodiment 10, wherein the solvent comprises pure water.

Embodiment 12: a method as in any of embodiments 9-11 wherein the ion exchange membrane is a homogeneous or heterogeneous membrane.

Embodiment 13: a method as in any of embodiments 9-12, wherein the electrodialysis treatment is performed in one electrodialysis cell, or in more than one electrodialysis cell in series.

Embodiment 14: the method of any one of embodiments 1-13, wherein the racemate is DL-pantoic acid lactone, the ionizable form of the first optical isomer is D-pantoic acid, and the nonionized form of the second optical isomer is L-pantoic acid lactone.

Embodiment 15: a method of making a polyhydroxy alcohol compound, comprising:

hydrogenating the hydroxyaldehyde obtained in step (a) to form a polyhydroxyl alcohol compound.

Embodiment 16: the method of embodiment 15 wherein the polyhydroxy alcohol compound is neopentyl glycol.

Embodiment 17: the method of embodiment 15 or 16, wherein the aldehyde comprises or consists of formaldehyde and isobutyraldehyde.

Embodiment 18: a process for preparing a polyhydroxy acid compound comprising:

oxidizing the hydroxyaldehyde obtained in step (a) to form a polyhydroxy acid compound.

Embodiment 19: the method of embodiment 18, wherein the polyhydroxy acid compound is hydroxypentanoic acid.

Embodiment 20: the method of embodiment 19, wherein the aldehyde comprises or consists of formaldehyde and isobutyraldehyde.

Embodiment 21: a method of preparing a hydroxyaldehyde comprising subjecting an aldehyde to an aldol condensation reaction in the presence of a first catalyst to obtain a hydroxyaldehyde, wherein at least one of the aldehydes is an aldehyde having an α -H, and the first catalyst is an immobilized catalyst comprising a solid support and a tertiary amine-based functional group.

Embodiment 22: the method of embodiment 21, wherein the aldehyde comprises formaldehyde and another aldehyde.

Embodiment 23: the method of embodiment 21 or 22, wherein the hydroxyaldehyde is selected from the group consisting of: dimethylolaldehyde, trimethylolacetaldehyde, 3-hydroxypropanal, 3-hydroxybutyraldehyde, 3-hydroxypentanal, 3-hydroxy-2-methylbutyraldehyde, 3-hydroxy-2-methylpentanal, 3-hydroxy-2-ethylhexanal, hydroxypivalaldehyde, and any combination thereof.

Embodiment 24: the method of embodiment 22 or 23, wherein the other aldehyde is selected from the group consisting of: acetaldehyde, propionaldehyde, n-butyraldehyde, isobutyraldehyde, pivalaldehyde, isovaleraldehyde, hexanal, octanal, 2-methylbutyraldehyde, 2-methylvaleraldehyde, 3-methylvaleraldehyde, 4-methylvaleraldehyde, glutaraldehyde, and any combination thereof.

Embodiment 25: the method according to any one of the preceding embodiments, wherein the solid support is selected from the group consisting of: resins and inorganic or organic materials comprising carbon, silicon or aluminum.

Embodiment 26: the method of embodiment 25, wherein the solid support is capable of withstanding temperatures above 60 ℃.

Embodiment 27: the method of embodiment 25 or 26, wherein the resin is subjected to a wash regeneration while the catalytic reaction is in progress.

Embodiment 28: the method of any one of embodiments 25-27, wherein the resin is selected from the group consisting of: styrene resins, polyarylethersulfone resins, silicone resins, epoxy resins, polyester resins, phenolic resins, alkyd resins, nitrocellulose, amino resins, acrylic resins, and polyurethane resins.

Embodiment 29: the method according to any one of the preceding embodiments, wherein the immobilized catalyst is selected from the group consisting of: photosensitive polyarylether containing tertiary amine functional groups on side chains, dimethylaminoethyl methacrylate-acrylonitrile copolymer, PSF-g-PDMAEMA and Si-MCM-41 tertiary amine carbon dioxide absorption film solid catalyst.

Embodiment 30: the method of embodiment 29, wherein the structures of the photosensitive poly (arylene ether) having tertiary amine functionality in its side chain, the dimethylaminoethyl methacrylate-acrylonitrile copolymer, and the PSF-g-PDMAEMA solid catalyst are:

embodiment 31: the method according to any one of the preceding embodiments, wherein the tertiary amine functional group is selected from the group consisting of: trimethylamine, triethylamine, tri-N-propylamine, tri-N-butylamine, methyldiethylamine, methyldiisopropylamine, dimethyl-t-butylamine, N' -tetramethylethylenediamine, and any combination thereof.

Embodiment 32: the method of any one of the preceding embodiments, wherein the tertiary amine-based functional group is covalently attached to the solid support.

Embodiment 33: the method of embodiment 32, wherein the tertiary amine functional group is covalently attached to the solid support via a linker.

Embodiment 34: the method of embodiment 33, wherein the linker is an aromatic group (optionally, phenyl), a saturated carbon chain, an ester chain, or a carbon ether chain.

Embodiment 35: the method of embodiment 34, wherein the immobilized catalyst is selected from the group consisting of: 270 resin with N, N-dimethylanilinium groups attached, 607 resin with N, N-dimethylanilinium groups attached, Merrifield resin with ethylpiperazine attached.

Embodiment 36: the method according to any one of the preceding embodiments, wherein the aldehyde is pre-mixed prior to contacting with the immobilized catalyst for aldol condensation reaction.

Embodiment 37: the method of any one of the preceding embodiments, wherein the reaction is carried out in a tank reactor or a microchannel reactor.

Embodiment 38: the method of any one of embodiments 22-37, wherein the molar ratio of formaldehyde to another aldehyde is from 1:0.9 to 1: 1.05.

Embodiment 39: the method according to any one of the preceding embodiments, wherein the reaction is carried out at a temperature of 60-130 degrees celsius, at a pressure of 1-5 MPa.

Embodiment 40: the method of any one of the preceding embodiments, further comprising isolating the resulting hydroxyaldehyde.

Embodiment 41: the method of any one of the preceding embodiments, wherein the hydroxyaldehyde is hydroxypivalaldehyde.

Embodiment 42: the method of any one of the preceding embodiments, wherein the aldehyde comprises or consists of formaldehyde and isobutyraldehyde.

Examples

In order that the present application may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting in any way.

The names of the first catalysts used in the following examples and their structures are shown in table 1.

Table 1: name and structure of the first catalyst

Some abbreviations of nouns mentioned in the examples are shown in Table 2.

Table 2: noun abbreviation

Example 1: screening of the first catalyst

Mixing isobutyraldehyde and formaldehyde, adding a first catalyst, and heating for reaction. And (3) performing gas phase analysis, if the content of isobutyraldehyde in the product is less than 1%, ending the reaction, otherwise, continuing the reaction until the reactant is remained qualified, and stopping heating to obtain colorless Hydroxypivalaldehyde (HPA) aqueous solution. Sampling and calculating the yield.

The type of the first catalyst added, the amount thereof and the experimental results are summarized in Table 3.

Table 3: screening of the first catalyst

As can be seen from Table 3, triethylamine, 270 resin and 607 resin are suitable for catalyzing aldol condensation reaction, wherein the catalytic efficiency of 270 resin and 607 resin is higher than that of triethylamine.

Example 2: exploring material ratio of formaldehyde and isobutyraldehyde and experimental results under different first catalysts

The inventor also explores the material ratio of formaldehyde to isobutyraldehyde and experimental results under different first catalysts. The specific procedure was similar to example 1, with formaldehyde: the molar ratio of isobutyraldehyde was 0.95:1, and triethylamine was used as a reference template for comparison. The results are summarized in Table 4. FIG. 1 shows a chromatogram of a gas phase analysis of the respective substances after the aldol condensation reaction is completed, when triethylamine is used as the first catalyst. FIG. 2 shows a chromatogram of a gas phase analysis of the respective substances after the aldol condensation reaction is completed, when 270 resin is used as the first catalyst. Comparison of FIG. 1 with FIG. 2 shows that when triethylamine is used as the first catalyst, the triethylamine peaks are increased in the product.

Table 4: material ratio of formaldehyde to isobutyraldehyde and experimental results under different first catalysts

As can be seen from Table 4, the molar ratio of formaldehyde to isobutyraldehyde is close to 1:1, and the total amount of impurities is relatively small.

Example 3: triethylamine, 270 resin and 607 resin are respectively used as first catalysts to respectively carry out kettle type reaction Preparation of hydroxypivalaldehyde by reactor reaction and microchannel reactor reaction

Example 3.1: kettle type reaction experiment operation with triethylamine as first catalyst

144g (2mol) of isobutyraldehyde and 167g (2.1mol) of 38 wt% formaldehyde are mixed, 6g of triethylamine are added, and the temperature is raised to 70-75 ℃ for reaction for 1 h. Through gas phase analysis, if the content of isobutyraldehyde in the product is less than 1%, the reaction is ended, otherwise, the reaction is continued until the reactant is remained qualified, and the heating is stopped, so that 310g of colorless Hydroxypivalaldehyde (HPA) aqueous solution is obtained, the yield is 90%, and the product is directly used for the next reaction. The resulting HPA became a white gypsum-like solid after standing at room temperature.

Example 3.2: tank type reaction experiment operation with 270 resin as first catalyst

144g (2mol) of isobutyraldehyde and 167g (2.1mol) of 38 wt% formaldehyde were mixed, 200g of treated LXT-270 resin (purchased from Xian blue, Xiao science and technology materials Co., Ltd., batch No. 20190802, washed with methanol, alkali, acid, alkali and water until the pH of the washing water was 9-10) was added, and the mixture was heated to 70-75 ℃ to react for 1 hour. And (3) analyzing the gas phase, if the content of isobutyraldehyde in the product is less than 1%, ending the reaction, otherwise, continuing the reaction until the reactant is remained qualified, stopping heating, and filtering while the reactant is hot. The resin is washed by 300g of deionized water for 1h at 70 ℃, filtered, washed by 100g of water for one time, and the washing water and the reaction liquid are combined to obtain a colorless solution HPA water solution, wherein the yield is 85 percent and the colorless solution is directly used for the next reaction. The resulting HPA became a white gypsum-like solid after standing at room temperature.

Example 3.3: kettle type reaction experiment operation with 607 resin as first catalyst

144g (2mol) of isobutyraldehyde and 167g (2.1mol) of 38 wt% formaldehyde were mixed, 160g of treated LXT-607 resin (purchased from Xian lan Xiao science and technology materials Co., Ltd., batch No. 20190912, washed with methanol, alkali, acid, alkali and water until the pH of the washing water was 9-10) was added, and the mixture was heated to 70-75 ℃ to react for 1 hour. And (3) analyzing the gas phase, if the content of isobutyraldehyde in the reactant is less than 1%, ending the reaction, otherwise, continuing the reaction until the reactant is remained qualified, stopping heating, and filtering while the reactant is hot. Washing the resin with 300g of deionized water at 70 ℃ for 1h, filtering, washing the resin with 100g of water, combining the washing water with the reaction solution to obtain a colorless solution HPA aqueous solution, wherein the yield is 90%, and the colorless solution is directly used for the next reaction. The resulting HPA product became a white gypsum-like solid after standing at room temperature.

Example 3.4: exploring microchannel reaction experimental conditions

The inventors have explored experimental conditions for microchannel reactions, including temperature, pressure, flow rate, etc. Specifically, isobutyraldehyde and formaldehyde are respectively led into a microchannel reactor through a liquid pump A and a liquid pump B, the temperature and the pressure of the reactor are adjusted, effluent liquid is collected, gas phase monitoring is carried out, and when the content of isobutyraldehyde in the effluent liquid is less than 1%, the isobutyraldehyde is a qualified product and can be directly used for the next reaction. The specific experimental conditions and results are summarized in table 5.

Table 5: micro-channel reaction experimental conditions (catalyst, temperature, pressure, flow rate and the like) and results

As can be seen from Table 5, when triethylamine was used as the catalyst, the preferable conditions for the microchannel experiment were 125 ℃ and 3MPa, the molar ratio of formaldehyde to isobutyraldehyde was 1:1.05, and the total flow rate was 10.4 ml/min. 270 resin as catalyst, the reaction conditions of the micro-channel experiment are preferably 125 ℃ and 2MPa, the molar ratio of formaldehyde to isobutyraldehyde is 1:1.05, and the total flow rate is 8.4 ml/min. 607 resin as catalyst, the reaction conditions of the micro-channel experiment are preferably 120 ℃ and 2MPa, the molar ratio of formaldehyde to isobutyraldehyde is 1:1.05, and the total flow rate is 8.4 ml/min.

Example 3.5: micro-channel reaction experimental operation using triethylamine as first catalyst

Sufficient 90 wt% of isobutyraldehyde is led into a microchannel reactor (purchased from micro-Kay chemical Co., Ltd.) through a liquid pump A at the speed of 4.3ml/min, simultaneously, sufficient 38% of formaldehyde solution containing 3.4 wt% of triethylamine is led into the microchannel reactor through a liquid pump B at the speed of 4ml/min, the temperature of the reactor is 120 ℃, the pressure is 2MPa, effluent liquid is collected, gas phase monitoring is carried out, and qualified products are obtained when the content of isobutyraldehyde in the effluent liquid is less than 1%, and the qualified products can be directly used for next reaction.

Example 3.6: microchannel reaction experimental operation using 270 resin as first catalyst

A sufficient amount of isobutyraldehyde was passed through a liquid pump A at a rate of 4.3ml/min into a microchannel reactor containing 330ml of LXT-270 resin (available from Seisan blue, New technology materials Co., Ltd., batch No. 20190802), and a sufficient amount of 38 wt% formaldehyde solution was passed through a liquid pump B at a rate of 4ml/min into the microchannel reactor, the reactor temperature was 120 ℃ and the pressure was 2MPa, and the effluent was collected and monitored in a gas phase, and when the isobutyraldehyde content in the effluent was < 1%, it was acceptable, it was directly used in the next reaction. And monitoring the effluent liquid every 30min, stopping when the content of isobutyraldehyde is more than 4%, pumping deionized water by double pumps to eject the residual products in the pipeline, regenerating the resin in the channel in an alkali washing and water washing mode, and continuously using the regenerated resin for the reaction.

Example 3.7: microchannel reaction experimental operation with 607 resin as first catalyst

A sufficient amount of isobutyraldehyde was passed through a liquid pump A at a rate of 4.3ml/min into a microchannel reactor containing 330ml of LXC-607 resin (available from Seisan blue, New technology materials Co., Ltd., batch No. 20190912), and a sufficient amount of 38 wt% formaldehyde solution was passed through a liquid pump B at a rate of 4ml/min into the microchannel reactor, the reactor temperature was 120 ℃ and the pressure was 2MPa, and the effluent was collected and monitored in a gas phase, and when the isobutyraldehyde content in the effluent was < 1%, it was judged as a good product, which was directly used in the next reaction. And monitoring the effluent liquid every 30min, stopping when the content of isobutyraldehyde is more than 4%, pumping deionized water by double pumps to eject the residual products in the pipeline, regenerating the resin in the channel in an alkali washing and water washing mode, and continuously using the regenerated resin for the reaction.

Example 4: application experiment of resin

Example 4.1: 270 resin application experiment

The same batch of 270 resin was recycled in the tank reactor with similar procedure as in example 3.2. Specific reaction conditions and results are shown in table 6.

Table 6: 270 resin application experiment

As can be seen from table 6, the 270 resin can be recycled at least three times, and ideally (e.g., if the post-treated resin is not lost), can be recycled indefinitely.

Example 4.2: 607 application experiment of resin

The same batch of 607 resin was recycled in the tank reactor with similar procedure as in example 3.3. Specific reaction conditions and results are shown in table 7.

Table 7: 607 experiment for resin application

As can be seen from table 7, the 607 resin can be recycled at least twice, and ideally (e.g., if the post-treated resin is not lost), can be recycled indefinitely.

Conclusion

The triethylamine has the same catalytic activity with 270 resin and 607 resin for aldol condensation reaction, but the triethylamine can not be completely recovered or removed, and finally the residual triethylamine is mixed in the wastewater, so that the wastewater is difficult to treat. 270 resin and 607 resin are fixed catalyst, there is no three wastes discharge problem, and the produced hydroxypivalaldehyde is easy to separate.

Although there are some side reactions during the aldol condensation reaction, the inventors have searched for a preferred method for preparing hydroxyaldehydes (e.g., hydroxypivalaldehyde) by adjusting various reaction conditions such as molar ratio of reactants (e.g., formaldehyde, isobutyraldehyde), reaction temperature, reaction pressure, kind and amount of catalyst, etc., thereby improving product yield, reducing production cost, and making the entire reaction process more environmentally friendly.

Example 5: preparation of DL-pantolactone racemate

Example 5.1

Synthesizing 102g (1mol) of Hydroxypivalaldehyde (HPA) without triethylamine by using 270 resin as a catalyst, adding 300ml of water, cooling to 0-5 ℃, slowly adding 48-49.5 g of cyanuric acid (HCN) (the molar ratio of HPA to HCN is 1: 0.98-1.01), controlling the reaction temperature to 0-10 ℃, stirring and reacting for 15 minutes after the hydrocyanic acid is added, removing and cooling, and adding 51g of concentrated sulfuric acid and heating to reflux for one hour. Cooled to below 40 ℃ and adjusted to pH 5.5 with ammonia. Layering, concentrating the upper layer liquid, distilling under reduced pressure, collecting 105-115 ℃ fractions to obtain 121g of yellowish liquid, namely the DL-pantolactone racemate, with the yield of 93.1%.

Example 5.2

Synthesizing 102g (1mol) of Hydroxypivalaldehyde (HPA) without triethylamine by using 270 resin as a catalyst, adding 150ml of water, cooling to 35 ℃, slowly dropwise adding 164g (1mol) of 30% sodium cyanide solution, cooling to 0-5 ℃, slowly dropwise adding 102g of concentrated sulfuric acid, heating to 100 ℃ after adding, reacting for 1h, cooling to 40 ℃ once, and adjusting the pH to 5.5 by using ammonia water. Layering, concentrating the upper layer liquid, distilling under reduced pressure, collecting 105-115 ℃ fractions to obtain 113g of yellowish liquid, namely the DL-pantolactone racemate, wherein the yield is 86.9%.

Example 6: electrodialysis method for splitting optical isomer in DL-pantolactone raceme

1. Preparation of enzyme conversion solution: 2L System, 600g of DL-pantolactone racemate prepared in example 5 was added, 300g of immobilized cells containing D-pantolactone hydrolase (pH7.0)&Mechanical stirring at 200rpm at 30 ℃ under 15N NH₃·H₂O titration is carried out to maintain the pH value to be 7.0, and the reaction is carried out for 3 hours;

2. pretreatment of the enzyme conversion solution: filtering with filter cloth, filtering with 0.2 μm microfiltration membrane, and filtering with 50KD ultrafiltration membrane;

3. electrodialysis separation: pumping the clear ultrafiltrate into a electrodialysis desalination chamber by using a homogeneous membrane stack B (the size is 10 x 30 cm; the membrane number is 5 pairs), putting 2L of pure water into a concentration chamber, adjusting the flow to ensure that the three chambers have equal pressure, and operating at constant pressure of 10V until the conductivity of the desalination chamber is less than 100 mu s/cm;

pumping the clear liquid in the concentration chamber into a desalting chamber of a secondary electrodialysis device, putting 2L of pure water in the concentration chamber, adjusting the flow rate to ensure that the three chambers have equal pressure, and operating at constant pressure of 10V until the conductivity of the desalting chamber is less than 100 mu s/cm;

4. concentration and acidification: pumping the clear liquid of the electrodialysis concentration chamber into concentration equipment, concentrating under reduced pressure to about 400ml, and adding sulfuric acid to about pH1 for lactonization;

5. and (3) crystallization: after concentration, the upper layer of the acidified solution was removed to give 259.2g of D-pantolactone in 43.2% yield (based on DL-pantolactone) and 98.9% ee by HPLC.

Example 7: electrodialysis method for splitting optical isomer in DL-pantolactone raceme

1. Preparation of enzyme conversion solution: 900g of DL-pantolactone racemate prepared in example 5 was added to a 3L system, and 90g of cells containing D-pantolactone hydrolase (pH 7.0) were added&Mechanical stirring at 200rpm at 30 ℃ under 15N NH₃·H₂O titration is carried out to maintain the pH value to be 7.0, and the reaction is carried out for 5 hours;

2. pretreatment of the enzyme conversion solution: centrifuging with a butterfly centrifuge, filtering with a 0.4 μm microfiltration membrane, and filtering with a 20KD ultrafiltration membrane;

3. electrodialysis separation: pumping the clear ultrafiltrate into a electrodialysis desalination chamber by using a heterogeneous membrane stack Z (the size: 10 x 20 cm; the membrane number is 10 pairs), putting 3L of pure water into a concentration chamber, adjusting the flow rate to ensure that the pressure of the concentration chamber is 3 times of that of the desalination chamber, and operating at constant pressure of 25V until the conductivity of the desalination chamber is less than 100 mu s/cm;

pumping the clear liquid in the concentration chamber into a desalting chamber of a secondary electrodialysis device, putting 3L of pure water in the concentration chamber, adjusting the flow rate to ensure that the pressure of the concentration chamber is 3 times of that of the desalting chamber, and operating at constant pressure of 25V until the conductivity of the desalting chamber is less than 100 mu s/cm; pumping the clear liquid in the concentration chamber into a desalting chamber of a three-stage electrodialysis device, putting 3L of pure water in the concentration chamber, adjusting the flow rate to ensure that the pressure of the concentration chamber is 3 times of that of the desalting chamber, and operating at constant pressure of 25V until the conductivity of the desalting chamber is less than 100 mu s/cm; pumping the clear liquid in the concentration chamber into a desalting chamber of a four-stage electrodialysis device, putting 3L of pure water in the concentration chamber, adjusting the flow rate to ensure that the pressure of the concentration chamber is 3 times of that of the desalting chamber, and operating at constant pressure of 25V until the conductivity of the desalting chamber is less than 100 mu s/cm;

4. concentration and acidification: pumping the clear liquid of the electrodialysis concentration chamber into concentration equipment, concentrating under reduced pressure to about 500ml, and adding sulfuric acid to about pH1 for lactonization;

5. and (3) crystallization: after concentration, the upper layer of the acidified solution was removed to give 364.5g of D-pantolactone in 40.5% yield (based on DL-pantolactone) and 97.6% ee by HPLC.

Other embodiments

Certain embodiments of the present application have been described above. It is expressly noted, however, that the present application is not limited to those embodiments, but rather, that additions and modifications to what is expressly described in the present application are intended to be included within the scope of the present application. Also, it is to be understood that the features of the various embodiments described herein are not mutually exclusive and can exist in various combinations and permutations, even if such combinations and permutations are not expressly stated, without departing from the spirit and scope of the application. Having described certain embodiments of the method of making hydroxyaldehydes, it will now become apparent to those skilled in the art that other embodiments incorporating the concepts of the present application can be used. Accordingly, the application should not be limited to certain embodiments, but rather should be limited only by the spirit and scope of the appended claims.

Claims

1. A method of resolving optical isomers from racemates by electrodialysis, comprising:

2. The method of claim 1, wherein the second catalyst comprises an enzyme composition.

3. The method of claim 2, wherein the enzyme composition comprises an ester hydrolase.

4. The method of claim 2 or 3, wherein the enzyme composition comprises a purified enzyme, a cell expressing an enzyme, or a lysate of a cell expressing an enzyme.

5. The method of any of claims 2-4, wherein the enzyme composition is immobilized on a substrate.

6. The method of any one of claims 1-5, further comprising after step (c) and before step (d): removing the residue of the second catalyst in the mixture.

7. The method of any one of claims 1-6, further comprising purifying and/or concentrating the isolated ionizable form of the first optical isomer, and/or purifying and/or concentrating the isolated nonionized form of the second optical isomer.

8. The method of any one of claims 1-7, further comprising converting the non-ionized form of the second optical isomer into the racemate.

9. A process as claimed in any one of claims 1 to 8, wherein the electrodialysis treatment is carried out in an electrodialysis cell having a depletion compartment and a concentration compartment separated by an ion exchange membrane.

10. A method as defined in claim 9, wherein the electrodialysis treatment comprises placing the mixture in the depletion compartment and a solvent in the concentration compartment, and energizing the electrodialysis cell causes the ionizable form of the first optical isomer in the depletion compartment to migrate into the solvent in the concentration compartment.