Continuous hydrogenation process of acetoacetate esters

Abstract

A continuous process for reducing an acetoacetate ester to a beta-hydroxybutyrate is disclosed herein. The continuous process includes contacting a mixture (M1) including an acetoacetate ester with hydrogen in the presence of a catalyst to obtain a mixture (M2) including a beta-hydroxybutyrate ester and collecting the beta-hydroxybutyrate ester.

Description

[0001] CONTINUOUS HYDROGENATION PROCESS OF ACETO AC ETATE ESTERS

[0002] CROSS-REFERENCE TO RELATED APPLICATION

[0003] This application is related and has right of priority to EP Application No. EP 24164842.7, filed on March 20, 2024, which is incorporated in its entirety for all purposes.

[0004] BACKGROUND

[0005] Acetoacetate esters and beta-hydroxy butyric acid (also referred to as “P-hydroxy-butyrate”; [3-hydroxyl butyric acid ester; beta-hydroxybutyl; BHB) esters prepared therefrom are valuable compounds with a wide variety of use, for example as parenteral nutrients or for the treatment of certain conditions, such as migraine headaches, Parkinson's, Alzheimer’s, and any other diseases related to the ketone metabolism of the brain.

[0006] US 2019 / 117612 A1 pertains to the field of migraine headaches and the management of the symptomology thereof using 3-hydroxybutyrate glycerides. US 2018 / 193300 A1 pertains to a method of treatment of mild to moderate nonpenetrating closed traumatic brain injury and mild to moderate traumatic brain injury due to surgical intervention using 3-hydroxybutyate glycerides.

[0007] Hence, ketone bodies like acetoacetate (AA) and [3-hydroxybutyrate (BHB) are believed to have a positive impact on brain health and may alleviate brain related disease and the associated symptoms. Therefore, it can be beneficial to supplement AA and / or BHB to improve brain health.

[0008] In the human body, AA and BHB are in a natural equilibrium wherein the interconversion of AA to BHB and BHB to AA is catalysed by the enzyme [3- hydroxybutyrate dehydrogenase involving nicotinamide adenine dinucleotide (NAD) (cf. for example H. Kolb et al. “Ketone bodies: from enemy to friend and guardian angel”, BMC Med., 2021 , 19(1 ), 313). The naturally occurring beta- hydroxybutyrate form is the enantiopure R-beta-hydroxybutyrate, which is the actual active form. However, it should be noted that there are beneficial effects of the S-enantiomeric form for potential diabetes treatment (A. Buga et. al. “Fasting and diurnal blood ketonemia and glycemia responses to a six-week, energy- controlled ketogenic diet, supplemented with racemic R / S-BHB salts” Clinical Nutrition, Volume 54, 2023, P227-287). Therefore, it is highly desirable to have synthetic methods in place to selectively synthesize the R-enantiomer or the S- enantiomer, either in an enantiopure or enantioenriched version.

[0009] In view of the natural equilibrium between AA and BHB in the human body, it can be desirable to supplement AA and BHB at the same time in order to maintain and respect the natural physiological equilibrium between BHB and AA when supplementing ketone bodies.

[0010] In general, molecules comprising AA units may be accessible via reacting diketene with an organic polyol or a [3-hydroxyl butyric acid ester of an organic polyol (WO 2023 / 094654). The respective AA units can be reduced to obtain BHB units. Notably, known methods of reducing AA units to obtain BHB units are conducted batch wise. However, many issues remain with batch production, as batch production may come along with several limitations such as limited productivity and reduced selectivity due to transesterifications and thermal decomposition of the acetoacetates.

[0011] Thus, in light of the limitations of batch producing BHB units, there is an ongoing need for excellent processes for the synthesis of (poly)alcohol esters comprising BHB. In particular, there is a need for efficient processes for the synthesis of (poly)alcohol esters comprising BHB that suitably are applicable under industrial scale. Further, there is a need for processes for the synthesis of (poly)alcohol esters comprising BHB in an enantiomeric excess such as in R- configuration. Further, there is a need for processes for the synthesis of said (poly)alcohol esters comprising BHB, wherein undesired side products are reduced.

[0012] SUMMARY

[0013] Other features and aspects of the present disclosure are discussed in greater detail below.

[0014] In general, the present disclosure is directed to a continuous process for reducing an acetoacetate ester to form a beta-hydroxy butyrate ester. The continuous process includes contacting a mixture (M1 ) including an acetoacetate ester with hydrogen in the presence of a catalyst to obtain a mixture (M2) including a beta-hydroxybutyrate ester and collecting the beta-hydroxybutyrate ester. In certain example embodiments, the mixture (M1 ) and the hydrogen are transferred through a reactor including the catalyst. The reactor may be a column reactor, a plug flow reactor, a fixed bed reactor, a trickle-bed reactor, a rotating bed reactor, a moving bed reactor, a coated reactor, a coated mixer, a heat exchanger, a static mixer, a slurry reactor, or a combination thereof.

[0015] In some example embodiments, the catalyst is a Ru-based catalyst. The Ru-based catalyst may be a Ru supported catalyst, Ru-Macho-BH (carbonylhydrido(tetrahydroborato)[bis(2- diphenylphosphinoethyl)amino]ruthenium(ll); CAS 1295649-41-0), (R)-RuCI[(p-Cymol)(SEGPHOS®)]CI (Chloro-[(R)-(+)-5,5'-bis- (diphenylphosphino)-4,4'-bi-1 ,3-benzodioxol]-(p-cymol)-ruthenium(ll)-chlorid; CAS 944451-28-9), (R)-RuCI[(p-Cymol)(BINAP)]CI (Chloro-[(R)-(+)-2,2'-bis- (diphenylphosphino)-l ,1 '-binaphthyl]-(p-cymol)-ruthenium(l)-chlorid; CAS 145926- 28-9), Ru-Macho® (also known as Carbonylchlorohy-drido{bis[2- (diphenylphosphinomethyl)ethyl]amino}ethyl]amino}ruthenium(ll); CAS 1295649- 40-9), or mixtures thereof. In preferred example embodiments, the Ru-based catalyst is a Ru supported catalyst, further wherein the Ru supported catalyst is a Ru / C.

[0016] In some example embodiments, the mixture (M1 ) further includes an organic solvent including a diethyl ether, MTBE, tetrahydrofurane, n-pentane, cyclopentane, n-hexane, cyclohexane, n-heptane, DMF, acetonitrile, toluene, chloroform, 1 ,4-dioxan, o / m / p-xylene, 2-methyltetrahydrofuran, cyclopentyl methyl ether, alcohols, alkyl alkynates, or mixtures thereof. In other example embodiments, the organic solvent includes an acetate ester, propionate ester, diethyl ether, MTBE, tetrahydrofurane, n-pentane, cyclopen-tane, n-hexane, cyclohexane, n-heptane, acetonitrile, toluene, chloroform, 1 ,4-dioxan, o / m / p- xylene, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methanol, ethanol, propanol, isopropanol, 1 -buntanol, sec-butyl alcohol, isobutanol, or mixtures thereof. In preferred example embodiments, the organic solvent includes an ethyl acetate, propyl acetate, butyl acetate, methyl propionate, ethyl propio-nate, propyl propionate, diethyl ether, MTBE, tetrahydrofurane, n-pentane, cyclopentane, n- hexane, cyclohexane, n-heptane, acetonitrile, toluene, chloroform, 1 ,4-dioxan, o / m / p-xylene, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methanol, ethanol, propanol, isopropanol, 1 -buntanol, sec-butyl alcohol, isobutanol, or mixtures thereof. In other example embodiments, the weight ratio of the organic solvent and the acetoacetate ester in the mixture (M1) is of about 10:1 to about 1 :10, such as about 6: 1 to about 1 :6, such as about 4: 1 to about 1 :4, such as about 3:1 to about 1 :3, such as about 2:1 to about 1 :2.

[0017] In certain example embodiments, contacting the mixture (M1 ) with the hydrogen in the presence of a catalyst is conducted at a temperature of about 15 °C to about 350 °C, preferably of about 20 °C to about 250 °C, more preferably of about 30 °C to about 200 °C, even more preferably of about 30 °C to about 150 °C, still more preferably of about 50 °C to about 120 °C, and in particular of about 55 °C to about 100 °C. In certain example embodiments, the mixture (M1 ) is contacted with the hydrogen in the presence of a catalyst at a temperature of about 50°C or greater, such as about 70° or greater. Thus, in other example embodiments, the mixture (M1 ) is contacted with the hydrogen in the presence of a catalyst at a temperature of about 50 °C to about 120 °C.

[0018] In some example embodiments, contacting the mixture (M1 ) including the acetoacetate ester with hydrogen in the presence of the catalyst to obtain a mixture (M2) including the beta-hydroxybutyrate ester further includes contacting the mixture (M1 ) with the hydrogen to obtain a mixture (M1a) and transferring the mixture (M1a) towards a reactor comprising the catalyst. In certain example embodiments, the reactor comprises a reactor mixture (CM) including a catalyst support, further wherein the catalyst includes a metal-based catalyst. In other example embodiments, the catalyst support includes SiO2 and / or AI2O3. In some example embodiments, the metal-based catalyst is a Ru-based catalyst.

[0019] In certain example embodiments, the weight ratio of the catalyst support and the catalyst in the reactor mixture (CM) is of about 100:0.5 to 1 :20, preferably of about 50: 1 to about 1 :10, more preferably of about 30: 1 to about 1 :2, even more preferably of about 20:1 about 1 :1 , still more preferably of about 10:1 to about 1 .5:1 , and in particular of about 6:1 to about 2:1 .

[0020] In other example embodiments, the continuous process has a residence time (e.g., the average length of time that the feed, or specifically a molecule in the feed, remains inside the reactor) of at least about 5 seconds to about 2 hours, more preferably of about 10 seconds to about 1 hour, and in particular of about 20 seconds to about 40 minutes.

[0021] In some example embodiments, contacting the mixture (M1 ) comprising the acetoacetate ester with hydrogen in the presence of the catalyst to obtain a mixture (M2) comprising the beta-hydroxybutyrate ester is conducted at an elevated pressure of about 1 to about 250 bar, more preferably of about 8 to about 140 bar, even more preferably of about 10 to about 130 bar, still more preferably of about 12 to about 120 bar, and in particular of about 15 to about 100 bar.

[0022] In certain example embodiments, the acetoacetate ester is a compound of formula 1 wherein A is derived from an organic alcohol, x is at least 1 , y is 0 or at least 1 , and n is 0 or an integer of 1 to 10. In other example embodiments, A is derived from an organic monohydric alcohol, wherein the organic monohydric alcohol comprises a methanol, ethanol, 1 -propanol, 2-propanol, 1 -butanol, 2-butanol, 2-methylpropan-

[0023] 1 -ol, 1 ,1 -dimethylethanol, 3-methylbutan-1 -ol, 2-methylbutan-1 -ol, 2,2- dimethylpropan-l-ol, pentan-3-ol, pen-tan-2-ol, 3-methylbutan-2-ol, 2-methylbutan-

[0024] 2-ol, hexan-1 -ol, hexan-2-ol, hexan-3-ol, 2-methylpentan-1 -ol, 3-methylpentan-1 -ol, 4-methylpentan-1 -ol, 2-methylpentan-2-ol, 3-methylpentan-2-ol, 4-methylpentan-2- ol, 2-methylpentan-3-ol, 3-methylpentan-3-ol, 2,2-dimethylbutan-1 -ol, 2,3- dimethylbutan-1 -ol, 3,3-dimethylbutan-1 -ol, 2,3-dimethylbutan-2-ol, 3,3- dimethylbutan-2-ol, 2-ethylbutan-1 -ol, 1 -heptanol, 2-heptanol, 3-heptanol, 4- heptanol, 1 -octanol, 2-octanol, nonal-1 -ol, decan-1 -ol, undecan-1 -ol, dodecan-1 -ol, tridecan-1 -ol, tetradecan-1 -ol, pentadecan-1 -ol, hexadecan-1 -ol, octadecan-1 -ol, hexacosan-1 -ol, triacontan-1 -ol, (hydroxymethyl)acrylate, or a combination thereof, x is 1 , and y is 0.

[0025] In some example embodiments, A is derived from an organic polyol, wherein the organic polyol includes a 1 ,4-butanediol, 1 ,6-hexanediol, neopentyl glycol, 4,8-bis(hydroxymethyl)tricyclo[5.2.1 . 02, 6]decane, 2-methyl-1 ,3 - propanediol, mono-, di-, tri- and tetraethylene glycol, polyethylene glycol, mono- di-, tri- and tetrapropylene glycol, polypropylene glycol, cyclohexane dimethanol, trimethylolethane, trimethylolpropane, ethoxylated trimethylolethane, propoxylated trimethylolethane, ethoxylated trimethylolpropane, propoxylated trimethylolpropane, pentaerythritol, glycerol, glycerol, or a combination thereof, and x + y is from 1 to the number of hydroxyl groups of the initial organic polyol A.

[0026] In other example embodiments, the acetoacetate ester is a compound of formula 1-2

[0027] 1-2

[0028] Wherein A is derived from an organic alcohol, x is an integer of 1 to 6, preferably of 1 to 4, more preferably of 1 to 3, and in particular of 1 to 2 or 1 , and y is 0 or at least 1 , preferably 0 or an integer of 1 to 4, more preferably 0 or an integer of 1 to 3, and in particular 0 or an integer of 1 to 2.

[0029] The inventor surprisingly found that the novel continuous process offers a high productivity and / or selectivity due to its short retention times at elevated temperatures.

[0030] BRIEF DESCRIPTION OF THE DRAWINGS

[0031] The present disclosure will be more readily appreciated by reference to the following detailed description when being considered in connection with the accompanying drawings in which:

[0032] Figure 1 is an exemplary, schematic view of a continuous process for the reduction of acetoacetate esters. The continuous process is conducted in an apparatus 100 comprising a reactor 4 comprising the catalyst.

[0033] Figure 2 is a further exemplary, schematic view of a continuous process for the reduction of acetoacetate esters. The continuous process is conducted in an apparatus 100 comprising a reactor 4 comprising the catalyst.

[0034] Figure 3 is a further exemplary, schematic view of a continuous process for the reduction of acetoacetate esters. The continuous process is conducted in an apparatus 100 comprising a reactor 4 comprising the catalyst. DEFINITIONS

[0035] In order for the present invention to be readily understood, several definitions of terms used in the course of the invention are set forth below.

[0036] The skilled person is well aware of the meaning “continuous process”. In general the term denotes that the process is not run in batch. Contrary to a batchbased process, the reaction is conducted in a continuous flow. Continuous flow means the process can run uninterrupted and frequent feedstock charging is not needed, as opposed to batch processes. A “batch process” generally refers to a process that involves a sequence of steps followed in a specific order, and which process has a beginning and an end. The present continuous process preferably refers to a process defined by a flow of reactants and products (for every step) wherein the process runs for a longer period of time while continuously feeding fresh reactants and continuously removing the product. Batch processing usually requires more energy, costs more money, and takes longer, but it is often considered to be a safe and manageable way to process certain compounds. Continuous processing, though efficient and cost-effective, is not always suitable for any chemical reaction.

[0037] According to the present invention, the term “linear or branched C2-12 alkyl” refers to a straight-chained or branched saturated hydrocarbon group having 2 to 12 carbon atoms, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms including methyl, ethyl, propyl, 1 -methylethyl, butyl, 1 -methylpropyl, 2-methylpropyl, 1 ,1- dimethylethyl, pentyl, 1 -methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2- dimethylpropyl, 1 -ethylpropyl, 1 ,1 -dimethylpropyl, 1 ,2-dimethylpropyl, hexyl, 1- methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1 ,1 -dimethylbutyl,

[0038] 1 .2-dimethylbutyl, 1 ,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,

[0039] 3.3-dimethylbutyl, 1 -ethylbutyl, 2-ethylbutyl, 1 , 1 ,2-trimethyl propyl, 1 ,2,2- trimethylpropyl, 1 -ethyl-1 -methylpropyl and 1-ethyl-2-methylpropyl.

[0040] According to the present invention, the term “alkanol” refers to alkyls, wherein at least one, preferably one, hydrogen is substituted with a hydroxyl group. Suitable alkanols are methanol, ethanol, propanol, isopropanol, 1 -buntanol, sec-butyl alcohol, isobutanol, and mixtures thereof. According to the present invention, the term “alkyl alkynate” refers to alkyl esters such as acetate esters (also referred to as alkyl acetate) or propionate esters (also referred to as alkyl propionate). Suitable alkyl alkynates are ethyl acetate, propyl acetate, butyl acetate, methyl propionate, ethyl propionate, propyl propionate, and mitres thereof.

[0041] According to the present invention, the term “C3-8 cycloalkyl” refers to a monocyclic saturated hydrocarbon group having 3 to 8 carbon ring members, such as 2, 3, 4, 5, 6, 7, or 8 carbon ring members, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0042] It is to be understood that the linear or branched C2-12 alkyl and C3-8 cycloalkyl may optionally be further substituted. Exemplary substituents include hydroxy, linear or branched C1-12 alkyl, C3-8 cycloalkyl, a carboxy group, halogen, and phenyl.

[0043] According to the present invention, the term “organic polyol” refers to a linear, branched, or cyclic organic compound with generally 2 to 18 carbon atoms having at least two hydroxyl groups, preferably at least three hydroxyl groups. As such, the organic polyol may have 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, or 18 carbon atoms. In one example embodiment, no more than one hydroxyl group is connected to one carbon atom. In one example embodiment, the organic polyol contains only carbon, hydrogen, and oxygen atoms.

[0044] According to the present invention, the term “at least three hydroxyl groups” means that the respective compound has three or more hydroxyl groups. In one example embodiment, “at least three hydroxyl groups” includes 3 to 18 hydroxyl groups such as 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, or 18 hydroxyl groups. In one example embodiment, “at least three hydroxyl groups” includes 3 to 12 hydroxyl groups such as 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12 hydroxyl groups. In one example embodiment, “at least three hydroxyl groups” includes 3 to 9 hydroxyl groups such as 3, 4, 5, 6, 7, 8, or 9 hydroxyl groups. In one example embodiment, “at least three hydroxyl groups” includes 3 to 6 hydroxyl groups such as 3, 4, 5, or 6 hydroxyl groups. Equally, the term “at least two hydroxyl groups” means that the respective compound has two or more hydroxyl groups. It is to be understood that if not explicitly stated otherwise, all stereoisomers, conformations and configurations are encompassed by compounds and functional groups which can be present as different stereoisomers or in different conformations and configurations. For example, the term “inositol” is to be understood as to include all stereoisomers and conformations such as myo-, scyllo-, muco-, D-chiro-, neo-inositol, L-chiro-, allo-, epi-, and c / s-inositol. For example, the term “hexanetriol” is to be understood as to include all hexane isomers including three hydroxyl groups such as 1 ,1 ,1 -hexanetriol, 1 ,1 ,2- hexanetriol, 1 ,2,2-hexanetriol, 1 ,2,3-hexanetriol, 1 ,2,4-hexanetriol, 1 ,2,5- hexanetriol, 1 ,2,6-hexanetriol, 1 ,3,5-hexanetriol, 1 ,3,6-hexanetriol, 2,3,4- hexanetriol, 2,3,5-hexanetriol etc.

[0045] It is to be understand that denotes the bond of the respective moiety to the remainder of the molecule.

[0046] As used herein, the term “comprising” is to be construed as encompassing both “including” and “consisting of”, both meanings being specifically intended, and hence individually disclosed, embodiments according to the present invention.

[0047] As used herein, the articles “a” and “an” preceding an element or component are intended to be nonrestrictive regarding the number of instances (i.e. occurrences) of the element or component. Therefore, “a” or “an” is to be read to include one or at least one, and the singular word form of the element or component also includes the plural unless the number is obviously meant to be singular.

[0048] As used herein, the term “about” modifying the quantity of a substance, ingredient, component, or parameter employed refers to variation in the numerical quantity that can occur, for example, through typical measuring and handling procedures, e.g., liquid handling procedures used for making concentrates or solutions. Furthermore, variation can occur from inadvertent error in measuring procedures, differences in the manufacture, source, or purity of the ingredients employed to carry out the methods, and the like. In one example embodiment, the term “about” means within 10% of the reported numerical value. In a more specific example embodiment, the term “about” means within 5% or within 2% of the reported numerical value. DETAILED DESCRIPTION

[0049] It is to be understood by one of ordinary skill in the art that the present discussion is a description of exemplary embodiments only and is not intended as limiting the broader aspects of the present disclosure.

[0050] In general, the present disclosure is directed to a continuous process for reducing an acetoacetate ester. The continuous process includes contacting a mixture (M1 ) comprising the acetoacetate ester with hydrogen in the presence of a catalyst to obtain a mixture (M2) comprising a beta-hydroxybutyrate ester and collecting the beta-hydroxybutyrate ester.

[0051] Without intending to be limited by theory, the present inventors have found that reducing an acetoacetate ester to a beta-hydroxybutyrate utilizing a continuous process may have several unexpected benefits over reducing an acetoacetate ester to a beta-hydroxybutyrate utilizing a batch process. For instance, the continuous process as described herein allows for more controlled and faster flow chemistry, thus resulting in higher temperatures, higher hydrogenation pressures, and shorter residence times being applied to the continuous process. Further, the continuous process as described herein can also have several additional environmental, safety, and economic advantages, as the continuous process allows for a reduction of the metal catalyst retained in the final product and a reduction in the amount of hydrogen need to successfully reduce the acetoacetate. Additionally, the continuous process as described herein requires significantly less purification steps to obtain the final beta-hydroxybutyrate product. Likewise, the continuous process of the present disclosure also may reduce the amount of thermal degradation or transesterification of the final beta- hydroxybutyrate product, as the continuous process allows for much quicker cooling of the final beta-hydroxybutyrate product compared to the batch process.

[0052] In the following, particular embodiments of the present invention such as moieties and reaction conditions are described in further details. It is to be understood that each embodiment is relevant on its own as well as in combination with other embodiments. In one example embodiment, the continuous process is fed with nitrogen. The continuous process may comprise at least one, at least two, at least three, or at least four nitrogen feeds, preferably two nitrogen feeds. In this connection, the nitrogen may be fed with a pressure of from about 2 to about 250 bar such as from about 2 to about 50 bar, preferably from about 3 to about 30 bar, and in particular from about 4 to about 10 bar or from about 2 to about 250 bar, preferably from about 20 to about 200 bar, and in particular from about 100 to about 150 bar.

[0053] For instance, Referring now to Figures 1-3, nitrogen feed 14 may have a pressure of from 1 to about 100 bar, preferably from about 2 to about 50 bar, more preferably from about 3 to about 30 bar, and in particular from about 4 to about 20 bar. Likewise, another nitrogen feed 12 may have a pressure of from about 20 to about 250 bar, preferably from about 50 to about 200 bar, more preferably from about 70 to about 180 bar, and in particular from about 90 to about 150 bar.

[0054] The continuous process is also fed with hydrogen. The continuous process may comprise one, two, three, or four hydrogen feeds, preferably one hydrogen feed. In this connection, the hydrogen may be fed with a pressure of from about 1 to about 250 bar, such as from about 20 to about 200 bar, preferably from about 50 to about 180 bar, more preferably from about 70 to about 150 bar, and in particular from about 80 to about 120 bar.

[0055] In one example embodiment, the hydrogen is adjusted as necessary. If the continuous process comprises at least two nitrogen feeds, the nitrogen may be fed with the same or different pressure, preferably with a different pressure. In certain example embodiments, only one nitrogen feed is utilized, depending on the desired reduction grade of the product. For instance, the hydrogen may be fed with a higher pressure than the nitrogen feed(s), such as about 75 bar or higher, such as about 80 bar or higher, such as about 85 bar or higher, such as about 90 bar or higher, such as about 95 bar or higher, and even such as 100 bar or higher.

[0056] For instance, in one example embodiment, contacting the mixture (M1 ) comprising the acetoacetate ester with hydrogen in the presence of the catalyst to obtain a mixture (M2) comprising the beta-hydroxybutyrate ester is conducted at elevated pressure, preferably at a pressure of about 1 to about 250 bar, more preferably of about 8 to about 140 bar, even more preferably of about 10 to about 130 bar, still more preferably of about 12 to about 120 bar, and in particular of about 15 to about 100 bar.

[0057] In one example embodiment, in the reactor comprising the catalyst is elevated pressure, preferably a pressure of about 1 to about 250 bar, more preferably of about 8 to about 140 bar, even more preferably of about 10 to about 130 bar, still more preferably of about 12 to about 120 bar, and in particular of about 15 to about 100 bar.

[0058] The continuous process as described herein may utilize hydrogen at a high pressure, which increases the speed of the reaction. Whereas, high pressures of hydrogenation would not be compatible with batch processes, as the many different steps required in known batch processes would render utilizing high pressures of hydrogenation undesirable, as it could lead to inconsistent results and safety concerns.

[0059] Additionally, the continuous process as disclosed herein may utilize reduced amounts of hydrogen as compared to other known batch processes, as the continuous process requires less input due to both the small size of the continuous reactors and the reduced number of steps in the process. Thus, the continuous process as described herein may result in more efficient use of inputs, such as hydrogen.

[0060] For instance, in one example embodiment, the molar amount of hydrogen in the continuous process is of about 1 to about 500 equivalents, preferably of about 1 to about 100 equivalents, more preferably of about 1 to about 10 equivalents, and in particular of about 1 to about 2 equivalents or of about 1 to about 1 .05 equivalents, of the total molar equivalents of acetoacetate groups of the acetoacetate ester.

[0061] In another example embodiment, the molar amount of hydrogen in the process is of about 0.1 to about 1 equivalents, preferably of about 0.2 to about 0.9 equivalents, more preferably of about 0.3 to about 0.7 equivalents, and in particular of about 0.4 to about 0.6 equivalents, of the total molar equivalents of acetoacetate groups of the acetoacetate ester.

[0062] In one example embodiment, the mixture (M1 ) and the hydrogen are transferred through a reactor comprising the catalyst. In a certain example embodiment, the mixture was contacted with a hydrogen flow before entering the reactor comprising the catalyst. The ability to add the hydrogen before the mixture contacts the catalyst is non-trivial. For instance, certain catalysts are more effective when there is a constant supply of hydrogen, as adding hydrogen to the catalyst once it has already contacted the mixture might deactivate the catalyst. Thus, in preferred embodiments, the hydrogen flow is contacted with the mixture before entering the reactor, as adding hydrogen to the mixture later in the process, as is normally done in batch processes, may reduce the effectiveness of the catalyst, and thus, the overall reaction.

[0063] In one example embodiment, the reactor is a heterogeneous catalytic reactor.

[0064] In one example embodiment, the reactor is a column reactor, a plug flow reactor, a fixed bed reactor, a trickle-bed reactor, a rotating bed reactor, a moving bed reactor, a coated reactor, a coated mixer, a heat exchanger, a static mixer, or a slurry reactor. It should be understood by one of ordinary skill in the art that any suitable reactor may be utilized.

[0065] In one example embodiment, the reactor is a fixed bed reactor (also called packed bed reactor), which can be any fixed bed reactor known in the art, for example including a reactor being a single cylindrical tube, but also a multitubular reactor, properly filled / packed with suitable catalyst(s). The catalyst bed, often in the form of pellets, extrudates or coated, is placed in such a way that it does not move with respect to the reactor itself. The reactants, including reactant gases, uniformly flow over the fixed catalyst bed. A specific type of fixed bed reactor for performing the present process is a trickle bed reactor. Trickle bed reactors comprise a family of reactors in which gas phase reactants react with liquid phase reactants while flowing over a bed of solid catalyst particles. The gas phase flow may be in any suitable direction.

[0066] Without intending to be limited by theory, the present inventors believe that utilizing a fixed bed reactor may have several benefits within the continuous process as disclosed herein. Notably, the present inventors believe that utilizing a fixed bed reactor may result in less catalyst required for the reduction of the acetoacetate ester. In certain example embodiments, the fixed bed reactor may facilitate higher degrees of contact between the catalyst and the acetoacetate ester. Further, the use of fixed bed reactors may also reduce the amount of metal in the final beta-hydroxybutyrate ester product, leading to higher quality products without additional tedious purification steps.

[0067] In one example embodiment, the catalyst is a metal-based catalyst. Preferably, the metal-based catalyst is a Ni-based catalyst, a Pd-based catalyst, a Pt-based catalyst, a Ru-based catalyst, a Co-based catalyst, an Ir-based catalyst, or a Rh-based catalyst.

[0068] In one example embodiment, when a metal-based catalyst is used, hydrogenation is performed in presence of a chiral ligand capable of forming complexes with the metal-based catalyst. Preferred chiral ligands include, but are not limited to, 2, 2'-bis(diphenylphosphino)-1 ,1 '-binaphthyl (BINAP), 1 , 1 '-Bi-2- naphthol (BINOL), 2,3-0-isopropylidene-2,3-dihydroxy-1 ,4- bis(diphenylphosphino)butane (DIOP), 2,2',5,5'-tetramethyl-4,4'-bis- (diphenylphoshino)-3,3’-bithiophene (tetraMe-BITlOP), Bis(di phenylphosphino)- 7,8-di hydro-6H-dibenzo[f,h][1 ,5]dioxonin(C3-TunePhos), 4,4'-Bis(bis(3,5- dimethylphenyl)phosphino)-2,2',6,6’-tetramethoxy-3,3'-bipyridine (Xyl-p-PHOS), (6,6'-Dimethoxybiphenyl-2,2'-diyl)-bis-(diphenylphosphin) (MeO-BIPHEP), and 1 ,2- Bis[(2-methoxyphenyl)phenylphosphino]ethane (DIPAMP).

[0069] By using a chiral ligand, the configuration of the R>-hydroxyl butyric acid ester units in the beta-hydroxybutyrate ester may be controlled.

[0070] In one example embodiment, the catalyst is a Ru-based catalyst. In certain example embodiments, the Ru-based catalyst is a Ru supported catalysts, Ru- Macho-BH (carbonylhydrido(tetrahydroborato)[bis(2- diphenylphosphinoethyl)amino]ruthenium(ll); CAS 1295649-41-0), (R)-RuCI[(p-Cymol)(SEGPHOS®)]CI (Chloro-[(R)-(+)-5,5'-bis- (diphenylphosphino)-4,4'-bi-1 ,3-benzodioxol]-(p-cymol)-ruthenium(ll)-chlorid; CAS 944451-28-9), (R)-RuCI[(p-Cymol)(BINAP)]CI (Chloro-[(R)-(+)-2,2'-bis- (diphenylphosphino)-l ,1 '-binaphthyl]-(p-cymol)-ruthenium(l)-chlorid; CAS 145926- 28-9), Ru-Macho® (also known as Carbonylchlorohydrido{bis[2- (diphenylphosphinomethyl)ethyl]amino}ethyl]amino}ruthenium(ll); CAS 1295649- 40-9), and mixtures thereof. In other example embodiments, the catalyst is a Ru supported catalyst, such as Ru / C.

[0071] When applying a homogenous catalyst, the reactor is preferably a micro reactor or a static mixer (e.g. comprising a mixing plate).

[0072] In one example embodiment, the mixture (M1 ) further comprises an organic solvent such as diethyl ether, MTBE, tetrahydrofurane, n-pentane, cyclopentane, n-hexane, cyclohexane, n-heptane, DMF, acetonitrile, toluene, chloroform, 1 ,4- dioxan, o / m / p-xylene, 2-methyltetrahydrofuran, cyclopentyl methyl ether, alcohols (e.g. alkanols), alkyl alkynates, and mixtures thereof. In preferred example embodiments, the organic solvent is an acetate ester (e.g. ethyl acetate, propyl acetate, butyl acetate, and the like), propionate ester (e.g. methyl propionate, ethyl propionate, propyl propionate, and the like), diethyl ether, MTBE, tetrahydrofurane, n-pentane, cyclopentane, n-hexane, cyclohexane, n-heptane, acetonitrile, toluene, chloroform, 1 ,4-dioxan, o / m / p-xylene, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methanol, ethanol, propanol, isopropanol, 1 -buntanol, sec-butyl alcohol, isobutanol, or a mixture thereof. In other preferred example embodiments, the organic solvent is ethyl acetate.

[0073] In one example embodiment, the weight ratio of the organic solvent the acetoacetate ester in the mixture (M1 ) is of about 10:1 to about 1 :10, more preferably of about 6:1 to about 1 :6, even more preferably of about 4:1 to about 1 :4, still more preferably of about 3: 1 to about 1 :3, and in particular of about 2: 1 to about 1 :2 such as about 1 :1.

[0074] In the event that no solvent is present, mixture (M1 ) can be added pure. Alternatively or in addition, the temperature and pressure may be adjusted (such as elevated) to reduce the viscosity of mixture (M1 ).

[0075] In one example embodiment, contacting the mixture (M1) with the hydrogen in the presence of a catalyst is conducted at a temperature of about 15 °C to about 350 °C, such as of about 20 °C to about 250 °C, preferably of about 30 °C to about 200 °C, more preferably of about 30 °C to about 150 °C, even more preferably of about 50 °C to about 120 °C, still more preferably of about 55 °C to about 100 °C, and in particular of about 60 °C to about 80 °C. Thus, in preferred example embodiments, the mixture (M1 ) is contacted with the hydrogen in the presence of a catalyst at a temperature of about 50 °C or more, such as about 55 °C or more, such as about 60 °C or more, such as about 65 °C or more, and even such as about 70 °C or more.

[0076] In one example embodiment, the contacting step comprises contacting the mixture (M1 ) with the hydrogen to obtain a mixture (M1a) and transferring the mixture (M1a) towards a reactor comprising the catalyst.

[0077] In one example embodiment, the reactor has a temperature of about 15 °C to about 200 °C, such as of about 20 °C to about 150 °C, preferably of about 30 °C to about 120 °C, more preferably of about 30 °C to about 110 °C, even more preferably of about 50 °C to about 100 °C, still more preferably of about 55 °C to about 90 °C, and in particular of about 60 °C to about 80 °C.

[0078] Thus, in preferred example embodiments, the reactor has a temperature of about 50 °C or more, such as about 55 °C or more, such as about 60 °C or more, such as about 65 °C or more, and even such as about 70 °C or more.

[0079] Without intending to be limited by theory, the present inventors believe that the continuous process as described herein may utilize temperatures that are higher than what may be utilized by batch processes. For instance, use of higher temperatures in the reactor may result in enhanced control of the flow chemistry, as elevating the temperature may allow for faster reaction rates, which prevents overheating and may ultimately lead to better and more predictable yields of beta- hydroxybutyrate ester.

[0080] Further, in a certain example embodiment, the continuous process as disclosed herein may utilize a combination of both elevated temperatures and pressure to control the flow chemistry. For instance, in an example embodiment, the hydrogen may be fed with a higher pressure, such as about 75 bar or higher, such as about 80 bar or higher, such as about 85 bar or higher, such as about 90 bar or higher, such as about 95 bar or higher, and even such as 100 bar or higher, in combination with a temperature that may be about 50 °C or greater, such as about 55 °C or greater, such as about 60 °C or greater, such as about 65 °C or greater, such as about 70 °C or greater. Thus, in preferred example embodiments, the continuous process has hydrogen fed with a higher pressure of about 80 bar to about 120 bar and has a temperature of about 60 °C to about 80 °C. Thus, in certain example embodiments, the present inventors believe elevating both the pressure and the temperature may result in increased flow chemistry.

[0081] In one example embodiment, mixture (M1 ) is preheated. This may be suitable to reduce the viscosity.

[0082] In one example embodiment, the reactor comprises a reactor mixture (CM) comprising a catalyst support and the catalyst, preferably a metal-based catalyst, and in particular a Ru-based catalyst.

[0083] Any suitable catalyst support can be used. The catalyst support can be selected from any support material that does not interfere with the current hydrogenation reaction. The hydrogenation catalyst may be supported on a carrier selected from SiC>2, SiO2-derived supports, carbon, silicon carbide, MAX-Phase (Ti2Al2C),TiO2, AI2O3, MgO, and ZrO2, preferably SiO2 and AI2O3.

[0084] In one example embodiment, the reactor (e.g. a column reactor) comprises a spacer such as sand.

[0085] In one example embodiment, the weight ratio of the catalyst support and the catalyst in the reactor mixture (CM) is of about 100:0.5 to 1 :20, preferably of about 50: 1 to about 1 :10, more preferably of about 30: 1 to about 1 :2, even more preferably of about 20:1 about 1 :1 , still more preferably of about 10:1 to about 1 .5:1 , and in particular of about 6:1 to about 2:1 .

[0086] In a further example embodiment, the weight ratio of the catalyst support and the catalyst in the reactor mixture (CM) is of about 100:1 to 1 .5:1 , preferably of about 50: 1 to about 2:1 , more preferably of about 30: 1 to about 2.5:1 , even more preferably of about 20:1 about 3:1 , still more preferably of about 10:1 to about 3.5:1 , and in particular of about 6:1 to about 4:1 .

[0087] In another example embodiment, the catalyst and the catalyst support are the same. In this connection, coated inserts may be mentioned.

[0088] In one example embodiment, the catalyst is present in the reactor of about 0.05 to about 100 wt.-% preferably of about 0.1 to about 40 wt.-% such as of about 5 to about 30 wt.-%, or of about 10 to about 25 wt.-%, or of about 15 to about 20 wt.-%, or of about 0.5 to about 6 wt.-%, based on the reactor mixture (CM). The commercially attractive time frame in which the present continuous process takes place, can be expressed in terms of “residence time”. The term “residence time” defines the average length of time that the feed, or specifically a molecule in the feed, remains inside the reactor, meaning herein inside the part that contains the catalyst. According to the process of the present invention, a residence time of equal or longer than 1 second up to equal to or less than 2 hours is desired. Preferably, the residence time is equal to or longer than 5 seconds up to equal to or less than 1 hour, preferably less than 30 minutes, or less than 15 minutes, or less than 10 minutes. For flow reactors suitable for the present hydrogenation reaction, the residence time may be varied by varying factors like the reactor volume, the feed flow rate (both of the mixture (M1 ) comprising the acetoacetate ester and of the hydrogen), the length of the catalyst bed, etc.. When compared to continuous processes, in a batch process, the residence time can be related to reaction time, i.e. how long a container is held at a specific temperature in the batch process.

[0089] In one example embodiment, the residence time is at least about 5 seconds, preferably of about 5 seconds to about 2 hours, more preferably of about 10 seconds to about 1 hour, even more preferably of about 20 seconds to about 40 minutes such as of about 1 to about 20 minutes.

[0090] In a certain example embodiment, the residence time may be minimized as a result of utilizing higher temperatures and / or higher pressures during the continuous process. The present inventors believe that minimizing residence time may result in enhanced optimization of the flow chemistry, as less residence time may minimize the formation of unwanted byproducts, thus resulting in more conversion of the final beta-hydroxybutyrate ester. Thus, in some example embodiments, the continuous process may have a residence time of about 20 minutes or less, such as about 10 minutes or less, such as about 5 minutes or less, such as about 2.5 minutes or less, and even such as about 1 minute or less.

[0091] In some example embodiments, the residence time of the continuous process may be at least about 10 minutes shorter than a residence time of a known batch process for the reduction of acetoacetate ester to beta- hydroxybutyrate ester, such as at least about 15 minutes shorter, such as at least about 20 minutes shorter, such as at least about 25 minutes shorter, such as at least about 30 minutes shorter, such as at least about 35 minutes shorter, such as at least about 40 minutes shorter.

[0092] The acetoacetate ester may be any organic compound comprising at least one acetoacetate group linked to the remainder of the compound via an ester. The acetoacetate ester may however also be any organic compound comprising at least two, such as two, three, four, five, six, seven, eight, nine, or ten, acetoacetate groups linked to the remainder of the compound via an ester.

[0093] The acetoacetate ester may also be referred to as (poly)alcohol comprising at least one acetoacetate group.

[0094] In one example embodiment, the acetoacetate ester is derived from an organic monohydric alcohol comprising one hydroxyl group. In this connection, it is to be understood that in an organic monohydric alcohol comprising one acetoacetate groups that is derived from an organic monohydric alcohol comprising one hydroxyl groups, the hydroxyl group is substituted by the respective acetoacetate group.

[0095] In one example embodiment, the acetoacetate ester is a polyalcohol comprising at least one acetoacetate group, which is derived from an organic polyol comprising at least 2 hydroxyl groups such as at least 3 hydroxyl groups. In this connection, it is to be understood that in a polyalcohol comprising at least one acetoacetate group that is derived from an organic polyol comprising at least 2 hydroxyl groups, at least one of said at least 2 hydroxyl groups are substituted by the respective acetoacetate group.

[0096] In one example embodiment, the organic polyol has from 2 to 10 hydroxyl groups. Preferably, the organic polyol has from 3 to 8 hydroxyl groups, such as from 3 to 7 hydroxyl groups, from 3 to 6 hydroxyl groups, from 3 to 5 hydroxyl groups, or from 3 to 4 hydroxyl groups.

[0097] In one example embodiment, the polyalcohol comprising at least one acetoacetate group comprises from 1 to 10 acetoacetate groups, preferably from 2 to 10 acetoacetate groups, more preferably from 3 to 8 acetoacetate groups, such as from 3 to 7 acetoacetate groups, from 3 to 6 acetoacetate groups, from 3 to 5 acetoacetate groups, or from 3 to 4 acetoacetate groups. The beta-hydroxybutyrate ester may be any organic compound comprising at least one beta-hydroxybutyrate group linked to the remainder of the compound via an ester. The beta-hydroxybutyrate ester may however also be any organic compound comprising at least two, such as two, three, four, five, six, seven, eight, nine, or ten, beta-hydroxybutyrate groups linked to the remainder of the compound via an ester.

[0098] In one example embodiment, the acetoacetate ester is a compound of formula 1 wherein

[0099] A is derived from an organic alcohol, x is at least 1 , y is 0 or at least 1 , and n is 0 or an integer of 1 to 10.

[0100] If the organic alcohol is an organic monohydric alcohols, it is to be understood that x is 1 , and y is 0.

[0101] If the organic alcohol is an organic polyol, x + y is from 2 to the number of hydroxyl groups of the initial organic polyol A.

[0102] In this connection, the beta-hydroxybutyrate ester may be a compound of formula 2 wherein

[0103] A is derived from an organic alcohol, x is at least 1 , y is 0 or at least 1 , n is 0 or 1 .

[0104] In one example embodiment n is 0 such as all n are 0.

[0105] In another example embodiment n is 1 such as all n are 1 .

[0106] In one example embodiment, the acetoacetate ester is a compound of formula 1-2

[0107] 1-2 wherein

[0108] A is derived from an organic alcohol, x is an integer of 1 to 6, preferably of 1 to 4, more preferably of 1 to 3, and in particular of 1 to 2 or 1 , and y is 0 or at least 1 , preferably 0 or an integer of 1 to 4, more preferably 0 or an integer of 1 to 3, and in particular 0 or an integer of 1 to 2.

[0109] In one example embodiment, the compound of formula 2 is a compound of formula 2-2

[0110] 2-2 and the acetoacetate ester is a compound of formula 1-2, 1-2

[0111] In one example embodiment, the compound of formula 2 is a compound of formula 2-3 and the acetoacetate ester is a compound of formula 1-2,

[0112] 1-2

[0113] In one example embodiment, the compound of formula 2 is a compound of formula 2-3a

[0114] 2-3a

[0115] In another example embodiment, the compound of formula 2 is a compound of formula 2-3b

[0116] 2-3b

[0117] In one example embodiment, the compound of formula 2 is a compound of formula 2-4 wherein

[0118] A is derived from an organic polyol, x is at least 1 , y is 0 or at least 1 , x + y is from 2 to the number of hydroxyl groups of the initial organic polyol A, and n is 0 or 1 ; and the acetoacetate ester is a compound of formula 1-4

[0119] 1-4.

[0120] In one example embodiment, the compound of formula 2-4 is a compound of formula 2-5

[0121] 2-5 and the compound of formula 1-4 is a compound of formula 1-5 1-5

[0122] In one example embodiment, the compound of formula 2-5 is a compound of formula 2-5a

[0123] 2-5a.

[0124] In one example embodiment, the compound of formula 2-5 is a compound of formula 2-5b

[0125] In one example embodiment, the compound of formula 2-5 is a compound of formula 2-5aa

[0126] 2-5aa and the compound of formula 1-5 is preferably a compound of formula 1-5aa

[0127] 1 -5aa. In one example embodiment, the compound of formula 2-5 is a compound of formula 2-5bb

[0128] 2-5bb and the compound of formula 1-5 is preferably a compound of formula 1-5bb

[0129] 1-5bb

[0130] In one example embodiment, x is at least 2, at least 3, or at least 4. In one example embodiment, x is 1 , 2, 3, 4, 5, or 6. Preferably, x is 2, 3, or 4.

[0131] In one example embodiment, y is 0, at least 1 , at least 2, at least 3, or at least 4. In a preferred example embodiment, y is 0.

[0132] In one example embodiment, x is 1 and y is 3. In one example embodiment, x is 2 and y is 2. In one example embodiment, x is 3 and y is 1 . In one example embodiment, x is 4 and y is 0.

[0133] In one example embodiment, x + y is from 2 to 10, such as from 3 to 10, from 3 to 8, from 3 to 7, from 3 to 6, from 3 to 5 or from 3 to 4. Accordingly, x + y may be 3, 4, 5, 6, 7, 8, 9, or 10, preferably 3, 4, 5, or 6.

[0134] In one example embodiment, x + y is equal to the number of hydroxyl groups of the initial polyol A. In one example embodiment, x + y is less than the number of hydroxyl groups of the initial polyol A.

[0135] The organic alcohol can comprise 1 , 2, 3, 4, 5 or 6 hydroxy functional groups, preferably comprises 1 , 2, 3 or 4 hydroxy functional groups. The organic alcohol can further comprise 1 , 2, 3 or 4 tertiary, non-aromatic amino functional groups.

[0136] When the organic alcohol comprises one hydroxyl functional group (organic monohydric alcohol), than the organic alcohol can be compound of formula (ALC-I) or compound of formula (ALC-II); wherein ruo is an integer from 2 to 30;

[0137] Ri6 is -(CH2)n2o- -(CH CH2O)n2iCH2CH2- or -(CH(CH3)CH2O)n22CH(CH3)CH2-; n2o is an integer from 2 to 10; n2iis an integer from 1 to 10; n22is an integer 0 to 10; preferably, n4o is an integer from 2 to 30;

[0138] Ri6 is -(CH2)n20- -(CH2CH2O)n2iCH2CH2- or -(CH(CH3)CH2O)n22CH(CH3)CH2-; n2o is an integer from 2 to 6; n2iis an integer from 1 to 5; n22is an integer 0 to 5; more preferably, n4o is an integer from 2 to 30;

[0139] R is -(CH2)n20- -(CH2CH2O)n2iCH2CH2-, or -(CH(CH3)CH2O)n22CH(CH3)CH2-; n2o is an integer from 2 to 4; ri2i is an integer from 1 to 3;

[0140] 022 is an integer 0 to 3; or, n4o is an integer from 3 to 30;

[0141] R is -(CH2)n2o- -(CH2CH2O)n2iCH2CH2- or -(CH(CH3)CH2O)n22CH(CH3)CH2-; n2o is an integer from 2 to 4; n2i is an integer from 1 to 3; n22 is an integer 0 to 3; or, n4o is an integer from 4 to 30;

[0142] R is -(CH2)n2o- -(CH2CH2O)n2iCH2CH2- or -(CH(CH3)CH2O)n22CH(CH3)CH2-; n2o is an integer from 2 to 4; n2i is an integer from 1 to 3; n22 is an integer 0 to 3;

[0143] Thus, in certain example embodiments, the organic alcohol is a methanol, ethanol, 1 -propanol, 2-propanol, 1 -butanol, 2-butanol, 2-methylpropan-1 -ol, 1 ,1 - dimethylethanol, 3-methylbutan-1 -ol, 2-methylbutan-1-ol, 2,2-dimethylpropan-l-ol, pentan-3-ol, pentan-2-ol, 3-methylbutan-2-ol, 2-methylbutan-2-ol, hexan-1 -ol, hexan-2-ol, hexan-3-ol, 2-methylpentan-1 -ol, 3-methylpentan-1 -ol, 4-methylpentan- 1 -ol, 2-methylpentan-2-ol, 3-methylpentan-2-ol, 4-methylpentan-2-ol, 2- methylpentan-3-ol, 3-methylpentan-3-ol, 2,2-dimethylbutan-1 -ol, 2,3- dimethylbutan-1 -ol, 3,3-dimethylbutan-1 -ol, 2,3-dimethylbutan-2-ol, 3,3- dimethylbutan-2-ol, 2-ethylbutan-1 -ol, 1 -heptanol, 2-heptanol, 3-heptanol, 4- heptanol, 1 -octanol, 2-octanol, nonal-1 -ol, decan-1 -ol, undecan-1 -ol, dodecan-1 -ol, tridecan-1 -ol, tetradecan-1 -ol, pentadecan-1 -ol, hexadecan-1 -ol, octadecan-1 -ol, hexacosan-1 -ol, triacontan-1 -ol, (hydroxymethyl)acrylate, or a combination thereof.

[0144] In one example embodiment, the organic alcohol comprises 2 or more hydroxyl functional groups (organic polyol). In one example embodiment, the organic polyol is a linear, branched, or cyclic organic compound with 2 to 18 carbon atoms having at least two hydroxyl groups, preferably at least three hydroxyl groups.

[0145] In one example embodiment, the organic polyol is selected from a linear or branched C2-12 alkyl substituted with at least 2 hydroxyl groups, preferably at least 3 hydroxyl groups, or a C3-8 cycloalkyl substituted with at least 2 hydroxyl groups, preferably at least 3 hydroxyl groups.

[0146] Preferably, the linear or branched C2-12 alkyl substituted with at least 2 hydroxyl groups, preferably at least 3 hydroxyl groups, is a glycerol, trimethylolpropane, butanetriol, 2-methyl-propanetriol, pentanetriol, 3-methyl- pentanetriol, hexanetriol, pentaerythritol, butanetetrol, pentanetetrol, hexanetetrol, hexanepentol, or a combination thereof.

[0147] Preferably, the C3-8 cycloalkyl substituted with at least 2 hydroxyl groups, preferably at least 3 hydroxyl groups, is a cyclopentanetriol, cyclohexanetriol, cyclopentanetetrol, cyclohexanetetrol, or a combination thereof. In a certain example embodiment, the C3-8 cycloalkyl substituted with at least 2 hydroxyl groups is a Cs cycloalkyl or a Ce cycloalkyl.

[0148] In one example embodiment, the organic polyol is a 1 ,4-butanediol, 1 ,6- hexanediol, neopentyl glycol, 4,8-bis(hydroxymethyl)tricyclo[5.2.1 ,02,6]decane, 2- methyl-1 ,3 -propanediol, mono-, di-, tri- and tetraethylene glycol, polyethylene glycol, mono-, di-, tri- and tetrapropylene glycol, polypropylene glycol, cyclohexane dimethanol, trimethylolethane, trimethylolpropane, ethoxylated trimethylolethane, propoxylated trimethylolethane, ethoxylated trimethylolpropane, propoxylated trimethylolpropane, pentaerythritol, or glycerol. In preferred example embodiments, the organic polyol is glycerol.

[0149] In one example embodiment, the organic polyol is a 1 ,4-butanediol, 1 ,6- hexanediol, neopentyl glycol, 4,8-bis(hydroxymethyl)tricyclo[5.2.1 ,02,6]decane, 2- methyl-1 ,3 -propanediol, mono-, di-, tri- and tetraethylene glycol, polyethylene glycol, mono-, di-, tri- and tetrapropylene glycol, polypropylene glycol, cyclohexane dimethanol, trimethylolethane, trimethylolpropane, ethoxylated trimethylolethane, propoxylated trimethylolethane, ethoxylated trimethylolpropane, propoxylated trimethylolpropane, pentaerythritol, glycerol, or a combination thereof. In preferred example embodiments, the organic polyol is glycerol, and x + y is from 1 to the number of hydroxyl groups of the initial organic polyol A.

[0150] In one example embodiment, the organic polyol is a monosaccharide, sugar alcohol, sugar acid, or a combination thereof.

[0151] Monosaccharides generally have the chemical formula CnH2nOn. Monosaccharides can be classified by the number x of carbon atoms they contain (CH20)X: trioses (x=3), tetroses (x=4), pentoses (x=5), hexoses (x=6) and heptoses (x=7).

[0152] In one example embodiment, the monosaccharide is selected from tetroses, pentoses, hexoses, heptoses, and combinations thereof. Preferably, the monosaccharide is selected from aldotetroses, ketotetroses, aldopentoses, ketopentoses, aldohexosen, ketohexoses, aldoheptoses, ketoheptoses, and combinations thereof.

[0153] In one example embodiment, the monosaccharide is an erythrose, threose, erythrulose, ribose, arabinose, xylose, lyxose, desoxyribose, ketopentose, ribulose, xylulose, allose, altrose, glucose, mannose, gulose, idose, galactose, talose, n-acetyl-d-glucosamin, glucosamin, N-acetyl-D-galactosamin, fucose, rhamnose, chinovose, fructose, 2-desoxy-D-glucose, fluordesoxyglucose, 6- desoxyfructose, 1 ,6-dichlorfructose, 3,6-anhydrogalactose, 1-O-methylgalactose, 1-O-methyl-D-glucose, 1-O-methyl-D-fructose, 3-O-methyl-D-fructose, 6-O-methyl- D-galactose, sedoheptulose, mannoheptulose, L-glycero-D-manno-heptose, or a combination thereof.

[0154] Sugar alcohols (also called polyhydric alcohols, polyalcohols, alditols or glycitols) are organic compounds, typically derived from sugars, containing one hydroxyl group (-OH) attached to each carbon atom.

[0155] In one example embodiment, the sugar alcohol is an erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, or a combination thereof.

[0156] A sugar acid is generally a monosaccharide with a carboxyl group at one end or both ends of the carbon chain. Main classes of sugar acids include aldonic acids, ulosonic acids, uronic acids, and aldaric acids. In aldonic acids, the aldehyde group (-CHO) located at the initial end (position 1 ) of an aldose is oxidized. In ulosonic acids, the -CH2(OH) group at the initial end of a 2-ketose is oxidized yielding an a-ketoacid. In uronic acids, the -CH2(OH) group at the terminal end of an aldose or ketose is oxidized. In aldaric acids, both ends (-CHO and -CH2(OH)) of an aldose are oxidized.

[0157] In one example embodiment, the sugar acid is selected from aldonic acids, ulosonic acids, uronic acids, aldaric acids, and combinations thereof. Preferably, the sugar acid is a xylonic acid, gluconic acid, ascorbic acid, neuraminic acid, ketodeoxyoctonic acid, glucuronic acid, galacturonic acid, iduronic acid, mucic acid, saccharic acid, or a combination thereof.

[0158] In one example embodiment, the organic polyol is a glycerol, sorbitol, xylitol, mannitol, erythritol, maltitol, glucose, glucitol, ribulose, pentaerythritol, trimethylolpropane, or a combinationthereof.

[0159] In one example embodiment, the compound of formula 2 is selected from the group consisting of

[0160] , and mixtures thereof.

[0161] In one example embodiment, the compound of formula 2 is selected from the group consisting of

[0162]

[0163] In one example embodiment, the [3-hydroxyl butyric acid ester groups of the beta-hydroxybutyrate ester are in form of a predominantly in S-configuration or predominantly in R-configuration. In one preferred example embodiment, all [3- hydroxyl butyric acid ester groups of the beta-hydroxybutyrate ester are in R- configuration. In another preferred example embodiment, all [3-hydroxyl butyric acid ester groups of the beta-hydroxybutyrate ester are in S-configuration.

[0164] In one example embodiment, the [3-hydroxyl butyric acid ester units of the beta-hydroxybutyrate ester are in form of a predominantly in S-configuration or predominantly in R-configuration. In one preferred example embodiment, all [3- hydroxyl butyric acid ester units of the beta-hydroxybutyrate ester are in R- configuration. In another preferred example embodiment, all [3-hydroxyl butyric acid ester units of the beta-hydroxybutyrate ester are in S-configuration.

[0165] As used herein, the term “[3-hydroxyl butyric acid ester units” is directed to the structures , whereas the term “[3-hydroxyl butyric acid ester groups” is directed

[0166] In one example embodiment, in the compound according to formula 2, all [3- hydroxyl butyric acid ester groups, preferably all [3-hydroxyl butyric acid ester units, are either D-configured or L-configured. In another example embodiment, all [3- hydroxyl butyric acid ester groups, preferably all [3-hydroxyl butyric acid ester units, are present in the compound according to formula 2 as a non-racemic mixture of D- and L- configurations.

[0167] In one example embodiment, the compound according to formula 2 contains more D-configured [3-hydroxyl butyric acid ester units than L-configured [3-hydroxyl butyric acid ester units. Preferably all [3-hydroxyl butyric acid ester groups, preferably all [3-hydroxyl butyric acid ester units, are in D-configuration.

[0168] In one example embodiment, in the compound according to formula 2, all [3- hydroxyl butyric acid ester groups, preferably all [3-hydroxyl butyric acid ester units, are either R-configured or S-configured. In another example embodiment, all [3- hydroxyl butyric acid ester groups, preferably all [3-hydroxyl butyric acid ester units, are present in the compound according to formula 2 as a non-racemic mixture of R- and S-configurations.

[0169] In one example embodiment, the compound according to formula 2 contains more R-configured [3-hydroxyl butyric acid ester units than S-configured [3-hydroxyl butyric acid ester units. Preferably all [3-hydroxyl butyric acid ester groups, preferably all [3-hydroxyl butyric acid ester units, are in R-configuration.

[0170] The final beta-hydroxybutyrate ester product of the continuous process may be obtained with little to no purification steps. As the continuous processes as described herein may utilize a fixed bed reactor, higher temperatures, and higher pressure, which allows for less metal catalyst left in the final product and process optimization, the continuous process may require significantly less purification steps to achieve the final beta-hydroxybutyrate product. For instance, in certain example embodiments, the continuous process may have about three or less purification steps (e.g., filtering, distillation, etc.), such as about two or less purification steps, such as about one or less purification steps. In a preferred example embodiment, the continuous process requires no additional purification steps to achieve the final beta-hydroxybutyrate product.

[0171] The present invention can be further understood by schematic Figure 1. In an apparatus 100, an acetoacetate ester (e.g. glyceryl acetoacetate (GlyAA)) can optionally be combined with an organic solvent (e.g. ethyl acetate). The organic solvent may be stored in container 18 and transferred towards pump 2 via a nitrogen flow, which may be introduced into the apparatus 100 via feed having a pressure of about 2 to about 50 bar, such as about 5 bar. The acetoacetate ester can be stored in container 1 and transferred towards pump 2 via a nitrogen flow, which may be introduced into the apparatus 100 via feed 14 having a pressure of about 2 to about 50 bar, such as about 5 bar. If the mixture comprises the acetoacetate ester and the organic solvent, the weight ratio of the acetoacetate ester to the organic solvent can be adjusted by the two pumps 2. The mixture comprising the acetoacetate ester and optionally the organic solvent can be transferred via the pumps 2 towards a catalyst (e.g. Ru supported catalyst) containing reactor 4. Before entering reactor 4, the mixture can be contacted with a hydrogen flow, which can be introduced into the apparatus 100 via feed 13. The hydrogen flow has a pressure of about 50 to about 200 bar, such as about 100 bar. In order to inert reactor 4 and / or for rinsing reactor 4, the apparatus 100 comprises nitrogen feed 12 having a pressure of about 70 to about 250 bar, such as about 120 bar. The Coriolis flow meter(s) 16 monitor the flow rates of the feeds 12, 13 and may be used in conjunction with the pumps 2 to control flow rate. Mass flow controller(s) 11 help control the flow of the feeds 12 and 13. The pressure sensor(s) 15 monitor system pressure and may be used for process control. Reactor 4 can be heated by oven 5 to a temperature of about 30 °C to about 150 °C, such as about 70 °C. Reactor 4 comprises the catalyst and may further comprise a catalyst support. The effective volume may be any suitable effective volume and depends on the reactor system and the desired product amount. The effective volume denotes the content in the reactor 4 that comprises the optional catalyst support and the catalysts such as Ru supported catalyst. When exiting the reactor 4, the mixture comprises a beta-hydroxybutyrate ester and optionally the organic solvent. The expansion vessel 10 may help stabilize system pressure of the apparatus 100. Said mixture passes the back pressure regulator 6 and the beta-hydroxybutyrate ester and the optional organic solvent is collected in container 7. Waste (including e.g. optional solvent and potentially unreacted starting material) is collected in containers 3 and 8 and excess of gas is released from the reactor by scrubber 9. Figure 2 demonstrates a similar apparatus 100 to Figure 1 , except that only one pump 2 is present and the weight ratio of the acetoacetate ester to the organic solvent can be premixed in container 1 before entering one pump 2.

[0172] Figure 3 demonstrates a similar apparatus 100 to Figure 1 , except that a heat exchanger 19 is placed within the apparatus 100 so that when the mixture including a beta-hydroxybutyrate ester and optionally the organic solvent is transferred from the reactor to the container 7 it is cooled at an increased rate. This expedited cooling may help prevent thermal degradation and transesterification of the final beta-hydroxybutyrate product.

[0173] It will be obvious for a person skilled in the art that these example embodiments and items only depict examples of a plurality of possibilities. Hence, the example embodiments shown here should not be understood to form a limitation of these features and configurations. Any possible combination and configuration of the described features can be chosen according to the scope of the invention.

[0174] The present invention will be further illustrated by the following examples.

[0175] COMPARATIVE EXAMPLE 1

[0176] In a clean autoclave, glyceryl acetoacetate (propane-1 ,2,3-triy tris(3- oxobutanoate); GlyAA) (1 eq.), ethyl acetate (5.4 eq.) and 6 wt.% Ru / C catalyst were mixed at 800 rpm. The reactor was charged with hydrogen (having a pressure of about 10 bar) and heated to 70 °C. The hydrogenation was stopped after 8 hours, and the reaction mixture was cooled to room temperature. The excess catalyst was filtered off. The reaction mixture was mixed with 20 wt.% activated charcoal and mixed at 800 rpm for 1 hour at room temperature. The charcoal was filtered off and washed with 10 wt.% ethyl acetate. 3-BHB was obtained as a slightly yellow-ish resin after LUWA-distillation at 100 °C and 60mbar. The resulting 3-BHB of the batch process had a conversion rate of approximately 90%.

[0177] COMPARATIVE EXAMPLE 2

[0178] Additional hydrogenations were performed in the same manner as described in Comparative Example 1 , except that certain components were varied according to Table 1 .

[0179] Table 1 : Additional batch hydrogenations.

[0180] As demonstrated by Comparative Examples 1-2, batch processes require higher temperatures to reduce the leaching of the Ru from the catalyst. However, higher temperatures in the batch process lead to decomposition of the acetoacetate ester starting material. Thus, to prevent decomposition, lower temperatures must be utilized. As shown by Table 1 , utilizing lower temperatures in the batch process may lead to leaching of the Ru. Thus, this would require additional tedious purification steps of the final 3-BHB product, including an extensive work-up with activated charcoal.

[0181] EXAMPLE 1

[0182] In an apparatus 100 (according to Figure 1 ), glyceryl acetoacetate (propane-1 ,2,3-triy tris(3-oxobutanoate); GlyAA) was combined with ethyl acetate. Ethyl acetate was stored in container 18 and transferred towards pump 2 via a nitrogen flow, which was introduced into the apparatus 100 via feed 14 (having a pressure of about 5 bar). GlyAA was stored in container 1 and transferred towards pump 2 via a nitrogen flow, which was introduced into the apparatus 100 via feed 14 (having a pressure of about 5 bar). The ratio of the GlyAA to the ethyl acetate was adjusted by the two pumps 2 to about 1 :1 The mixture comprising the GlyAA and ethyl acetate was transferred via the pumps 2 towards a Ru / C containing column reactor 4. The mixture flow (comprising the GlyAA and ethyl acetate) was about Qv = 0.3 mL / min and about Qm = 0.31 g / min. Before entering column reactor 4, the mixture was contacted with a hydrogen flow, which was introduced into the apparatus 100 via feed 13 (having a pressure of about 100 bar). The hydrogen flow was adjusted to provide six equivalents, which corresponds to a Qv of about 66 mLn / min. Inerting and rinsing was conducted with nitrogen feed 12 (having a pressure of about 120 bar). Column reactor 4 was heated by oven 5 to a temperature of about 70 °C and a pressure of about 20 bar was applied thanks to the back pressure regulator 6 (BPR). Column reactor 4 comprised a 5 wt.% Ru / C catalyst. The effective volume was 26.7 mL comprising 18.89 g Ru / C. The total volume of the column reactor 4 was 26.7 mL and the column reactor 4 had a length of about 250 mm. The column reactor 4 was packed with full Ru / C catalyst. When exiting the column reactor 4, the mixture comprised a beta-hydroxybutyrate ester and ethyl acetate. Said mixture passed the BPR 6 and the beta- hydroxybutyrate ester (i.e. propane-1 ,2,3-triy tris(beta-hydroxybutyrate); 3-BHB) and ethyl acetate was collected in container 7. Waste was collected in container 8 and excess of gas was released from the apparatus 100 by scrubber 9. 3-BHB was produced with a productivity of about 432 g / L / h (mass / volume of reactor / time) and a conversion over 95%.

[0183] EXAMPLE 2

[0184] Additional hydrogenations were performed in the same manner as described in Example 1 , except that certain components were varied according to Table 2. The additional hydrogenations according to Table 2 were conducted, wherein 5 wt.% Ru / C was applied, the starting material flow feed was 0.6 mL / min, and rt (retention time) was about 66 min.

[0185] Table 2: Additional continuous hydrogenations. EXAMPLE EMBODIMENTS

[0186] Example Embodiment 1 : A continuous process for reducing an acetoacetate ester, the continuous process comprising: contacting a mixture (M1 ) comprising an acetoacetate ester with hydrogen in the presence of a catalyst to obtain a mixture (M2) comprising a beta-hydroxybutyrate ester; collecting the beta-hydroxybutyrate ester.

[0187] Example Embodiment 2: The continuous process according to example embodiment 1 , wherein the mixture (M1 ) and the hydrogen are transferred through a reactor comprising the catalyst.

[0188] Example Embodiment 3: The continuous process according to any preceding example embodiment, wherein the reactor is a column reactor, a plug flow reactor, a fixed bed reactor, a trickle-bed reactor, a rotating bed reactor, a moving bed reactor, a coated reactor, a coated mixer, a heat ex-changer, a static mixer, a slurry reactor, or a combination thereof.

[0189] Example Embodiment 4: The continuous process according to any preceding example embodiment, wherein the catalyst is a Ru-based cata-lyst.

[0190] Example Embodiment 5: The continuous process according to any preceding example embodiment, wherein the Ru-based catalyst is a Ru supported catalyst, Ru-Macho-BH (carbonylhydrido(tetrahydroborato)[bis(2- diphenylphosphinoethyl)amino]ruthenium(ll); CAS 1295649-41-0), (R)-RuCI[(p-Cymol)(SEGPHOS®)]CI (Chloro-[(R)-(+)-5,5'-bis- (diphenylphosphino)-4,4'-bi-1 ,3-benzodioxol]-(p-cymol)-ruthenium(ll)-chlorid; CAS 944451-28-9), (R)-RuCI[(p-Cymol)(BINAP)]CI (Chloro-[(R)-(+)-2,2'-bis- (diphenylphosphino)-l ,1 '-binaphthyl]-(p-cymol)-ruthenium(l)-chlorid; CAS 145926- 28-9), Ru-Macho® (also known as Carbonylchlorohy-drido{bis[2- (diphenylphosphinomethyl)ethyl]amino}ethyl]amino}ruthenium(ll); CAS 1295649- 40-9), or mixtures thereof. Example Embodiment 6: The continuous process according to any preceding example embodiment, wherein the Ru-based catalyst is a Ru supported catalyst, further wherein the Ru supported catalyst is a Ru / C.

[0191] Example Embodiment 7: The continuous process according to any preceding example embodiment, wherein the mixture (M1 ) further comprises an organic solvent including a diethyl ether, MTBE, tetrahydrofurane, n-pentane, cyclopentane, n-hexane, cyclohexane, n-heptane, DMF, acetonitrile, toluene, chloroform, 1 ,4-dioxan, o / m / p-xylene, 2-methyltetrahydrofuran, cyclopentyl methyl ether, alcohols, alkyl alkynates, or mixtures thereof.

[0192] Example Embodiment 8: The continuous process according to any preceding example embodiment, wherein the organic solvent includes an acetate ester, propionate ester, diethyl ether, MTBE, tetrahydrofurane, n-pentane, cyclopen-tane, n-hexane, cyclohexane, n-heptane, acetonitrile, toluene, chloroform, 1 ,4-dioxan, o / m / p-xylene, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methanol, ethanol, propanol, isopropanol, 1 -buntanol, sec-butyl alcohol, isobutanol, or mixtures thereof.

[0193] Example Embodiment 9: The continuous process according to any preceding example embodiment, wherein the organic solvent includes an ethyl acetate, propyl acetate, butyl acetate, methyl propionate, ethyl propio-nate, propyl propionate, diethyl ether, MTBE, tetrahydrofurane, n-pentane, cyclopentane, n- hexane, cyclohexane, n-heptane, acetonitrile, toluene, chloroform, 1 ,4-dioxan, o / m / p-xylene, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methanol, ethanol, propanol, isopropanol, 1 -buntanol, sec-butyl alcohol, isobutanol, or mixtures thereof.

[0194] Example Embodiment 10: The continuous process according to any preceding example embodiment, wherein the weight ratio of the organic solvent and the acetoacetate ester in the mixture (M1 ) is of about 10:1 to about 1 :10, such as about 6:1 to about 1 :6, such as about 4:1 to about 1 :4, such as about 3:1 to about 1 :3, such as about 2:1 to about 1 :2.

[0195] Example Embodiment 11 : The continuous process according to any preceding example embodiment, wherein contacting the mixture (M1) with the hydrogen in the presence of a catalyst is conducted at a temperature of about 15 °C to about 350 °C, preferably of about 20 °C to about 250 °C, more preferably of about 30 °C to about 200 °C, even more preferably of about 30 °C to about 150 °C, still more preferably of about 50 °C to about 120 °C, and in particular of about 55 °C to about 100 °C.

[0196] Example Embodiment 12: The continuous process according to any preceding example embodiment, wherein the temperature is about 50 °C to about 120 °C.

[0197] Example Embodiment 13: The continuous process according to any preceding example embodiment, wherein contacting the mixture (M1) comprising the acetoacetate ester with hydrogen in the presence of the catalyst to obtain a mixture (M2) comprising the beta-hydroxybutyrate ester further comprises contacting the mixture (M1 ) with the hydrogen to obtain a mixture (M1a) and transferring the mixture (M1a) towards a reactor comprising the catalyst.

[0198] Example Embodiment 14: The continuous process according to any preceding example embodiment, wherein the reactor comprises a reactor mixture (CM) comprising a catalyst support, further wherein the catalyst comprises a metalbased catalyst.

[0199] Example Embodiment 15: The continuous process according to any preceding example embodiment, wherein the catalyst support includes SiO2 and / or AI2O3.

[0200] Example Embodiment 16: The continuous process according to any preceding example embodiment, wherein the metal-based catalyst is a Ru-based catalyst. Example Embodiment 17: The continuous process according to any preceding example embodiment, wherein the weight ratio of the catalyst support and the catalyst in the reactor mixture (CM) is of about 100:0.5 to 1 :20, preferably of about 50: 1 to about 1 :10, more preferably of about 30: 1 to about 1 :2, even more preferably of about 20:1 about 1 :1 , still more preferably of about 10:1 to about 1 .5:1 , and in particular of about 6:1 to about 2:1 .

[0201] Example Embodiment 18: The continuous process according to any preceding example embodiment, wherein the continuous process has a residence time of at least about 5 seconds to about 2 hours, more preferably of about 10 seconds to about 1 hour, and in particular of about 20 seconds to about 40 minutes.

[0202] Example Embodiment 19: The continuous process according to any preceding example embodiment, wherein the residence time is about 20 seconds to about 40 minutes.

[0203] Example Embodiment 20: The continuous process according to any preceding example embodiment, wherein contacting the mixture (M1) comprising the acetoacetate ester with hydrogen in the presence of the catalyst to obtain a mixture (M2) comprising the beta-hydroxybutyrate ester is conducted at an elevated pressure of about 1 to about 250 bar, more preferably of about 8 to about 140 bar, even more preferably of about 10 to about 130 bar, still more preferably of about 12 to about 120 bar, and in particular of about 15 to about 100 bar.

[0204] Example Embodiment 21 : The continuous process according to any preceding example embodiment, wherein the elevated pressure is about 12 to about 120 bar.

[0205] Example Embodiment 22: The continuous process according to any preceding example embodiment, wherein the acetoacetate ester is a compound of formula 1 wherein A is derived from an organic alcohol, x is at least 1 , y is 0 or at least 1 , and n is 0 or an integer of 1 to 10.

[0206] Example Embodiment 23: The continuous process according to any preceding example embodiment, wherein A is derived from an organic monohydric alcohol, wherein the organic monohydric alcohol comprises a methanol, ethanol, 1- propanol, 2-propanol, 1 -butanol, 2-butanol, 2-methylpropan-1-ol, 1 ,1- dimethylethanol, 3-methylbutan-1-ol, 2-methylbutan-1-ol, 2,2-dimethylpropan-l-ol, pentan-3-ol, pen-tan-2 -ol, 3-methylbutan-2-ol, 2-methylbutan-2-ol, hexan-1-ol, hexan-2-ol, hexan-3-ol, 2-methylpentan-1-ol, 3-methylpentan-1-ol, 4-methylpentan- 1 -ol, 2-methylpentan-2-ol, 3-methylpentan-2-ol, 4-methylpentan-2-ol, 2- methylpentan-3-ol, 3-methylpentan-3-ol, 2,2-dimethylbutan-1-ol, 2,3- dimethylbutan-1-ol, 3,3-dimethylbutan-1-ol, 2,3-dimethylbutan-2-ol, 3,3- dimethylbutan-2-ol, 2-ethylbutan-1-ol, 1 -heptanol, 2-heptanol, 3-heptanol, 4- heptanol, 1 -octanol, 2-octanol, nonal-1-ol, decan-1 -ol, undecan-1-ol, dodecan-1-ol, tridecan-1-ol, tetradecan-1-ol, pentadecan-1 -ol, hexadecan-1 -ol, octadecan-1 -ol, hexacosan-1-ol, triacontan-1-ol, (hydroxymethyl)acrylate, or a combination thereof, x is 1 , and y is 0.

[0207] Example Embodiment 24: The continuous process according to any preceding example embodiment, wherein A is derived from an organic polyol, wherein the organic polyol includes a 1 ,4-butanediol, 1 ,6-hexanediol, neopentyl glycol, 4,8- bis(hydroxymethyl)tricyclo[5.2.1 . 02, 6]decane, 2-methyl-1 ,3 -propanediol, mono- di-, tri- and tetraethylene glycol, polyethylene glycol, mono-, di-, tri- and tetrapropylene glycol, polypropylene glycol, cyclohexane dimethanol, trimethylolethane, trimethylolpropane, ethoxylated trimethylolethane, propoxylated trimethylolethane, ethoxylated trimethylolpropane, propoxylated trimethylolpropane, pentaerythritol, glycerol, glycerol, or a combination thereof, and x + y is from 1 to the number of hydroxyl groups of the initial organic polyol A.

[0208] Example Embodiment 25: The continuous process according to any preceding example embodiment, wherein the acetoacetate ester is a compound of formula 1- 2

[0209] 1-2 wherein A is derived from an organic alcohol, x is an integer of 1 to 6, preferably of 1 to 4, more preferably of 1 to 3, and in particular of 1 to 2 or 1 , and y is 0 or at least 1 , preferably 0 or an integer of 1 to 4, more preferably 0 or an integer of 1 to 3, and in particular 0 or an integer of 1 to 2.

Claims

What Is Claimed:1 . A continuous process for reducing an acetoacetate ester, the continuous process comprising: contacting a mixture (M1 ) comprising an acetoacetate ester with hydrogen in the presence of a catalyst to obtain a mixture (M2) comprising a beta-hydroxybutyrate ester; collecting the beta-hydroxybutyrate ester.

2. The continuous process according to claim 1 , wherein the mixture (M1 ) and the hydrogen are transferred through a reactor comprising the catalyst.

3. The continuous process according to claim 2, wherein the reactor is a column reactor, a plug flow reactor, a fixed bed reactor, a trickle-bed reactor, a rotating bed reactor, a moving bed reactor, a coated reactor, a coated mixer, a heat ex-changer, a static mixer, a slurry reactor, or a combination thereof.

4. The continuous process according to claim 1 , wherein the catalyst is a Ru-based catalyst.

5. The continuous process according to claim 4, wherein the Ru-based catalyst is a Ru supported catalyst, Ru-Macho-BH (carbonylhydrido(tetrahydroborato)[bis(2- diphenylphosphinoethyl)amino]ruthenium(ll); CAS 1295649-41-0), (R)-RuCI[(p-Cymol)(SEGPHOS®)]CI (Chloro-[(R)-(+)-5,5'-bis- (diphenylphosphino)-4,4'-bi-1 ,3-benzodioxol]-(p-cymol)-ruthenium(ll)-chlorid; CAS 944451-28-9), (R)-RuCI[(p-Cymol)(BINAP)]CI (Chloro-[(R)-(+)-2,2'-bis- (diphenylphosphino)-l ,1 '-binaphthyl]-(p-cymol)-ruthenium(l)-chlorid; CAS 145926- 28-9), Ru-Macho® (also known as Carbonylchlorohy-drido{bis[2- (diphenylphosphinomethyl)ethyl]amino}ethyl]amino}ruthenium(ll); CAS 1295649- 40-9), or mixtures thereof.

6. The continuous process according to claim 5, wherein the Ru-based catalyst is a Ru supported catalyst, further wherein the Ru supported catalyst is a Ru / C.

7. The continuous process according to claim 1 , wherein the mixture (M1 ) further comprises an organic solvent including a diethyl ether, MTBE, tetrahydrofurane, n-pentane, cyclopentane, n-hexane, cyclohexane, n-heptane,DMF, acetonitrile, toluene, chloroform, 1 ,4-dioxan, o / m / p-xylene, 2- methyltetrahydrofuran, cyclopentyl methyl ether, alcohols, alkyl alkynates, or mixtures thereof.

8. The continuous process according to claim 7, wherein the organic solvent includes an acetate ester, propionate ester, diethyl ether, MTBE, tetrahydrofurane, n-pentane, cyclopen-tane, n-hexane, cyclohexane, n-heptane, acetonitrile, toluene, chloroform, 1 ,4-dioxan, o / m / p-xylene, 2- methyltetrahydrofuran, cyclopentyl methyl ether, methanol, ethanol, propanol, isopropanol, 1 -buntanol, sec-butyl alcohol, isobutanol, or mixtures thereof.

9. The continuous process according to claim 7, wherein the organic solvent includes an ethyl acetate, propyl acetate, butyl acetate, methyl propionate, ethyl propio-nate, propyl propionate, diethyl ether, MTBE, tetrahydrofurane, n- pentane, cyclopentane, n-hexane, cyclohexane, n-heptane, acetonitrile, toluene, chloroform, 1 ,4-dioxan, o / m / p-xylene, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methanol, ethanol, propanol, isopropanol, 1 -buntanol, sec-butyl alcohol, isobutanol, or mixtures thereof.

10. The continuous process according to claim 7, wherein the weight ratio of the organic solvent and the acetoacetate ester in the mixture (M1 ) is of about 10:1 to about 1 :10.11 . The continuous process according to claim 1 , wherein contacting the mixture (M1 ) with the hydrogen in the presence of a catalyst is conducted at a temperature of about 15 °C to about 350 °C.

12. The continuous process according to claim 11 , wherein the temperature is about 50 °C to about 120 °C.

13. The continuous process according to claim 1 , wherein contacting the mixture (M1 ) comprising the acetoacetate ester with hydrogen in the presence of the catalyst to obtain a mixture (M2) comprising the beta-hydroxybutyrate ester further comprises: contacting the mixture (M1 ) with the hydrogen to obtain a mixture (M1a) and transferring the mixture (M1a) towards a reactor comprising the catalyst.

14. The continuous process according to claim 2, wherein the reactor comprises a reactor mixture (CM) comprising a catalyst support, further wherein the catalyst comprises a metal-based catalyst.

15. The continuous process according to claim 14, wherein the catalyst support includes SiO2 and / or AI2O3.

16. The continuous process according to claim 14, wherein the metalbased catalyst is a Ru-based catalyst.

17. The continuous process according to claim 14, wherein the weight ratio of the catalyst support and the catalyst in the reactor mixture (CM) is of about 100:0.5 to 1 :20.

18. The continuous process according to claim 2, wherein the continuous process has a residence time of at least about 5 seconds to about 2 hours.

19. The continuous process according to claim 18, wherein the residence time is about 20 seconds to about 40 minutes.

20. The continuous process according to claim 1 , wherein contacting the mixture (M1 ) comprising the acetoacetate ester with hydrogen in the presence of the catalyst to obtain a mixture (M2) comprising the beta-hydroxybutyrate ester is conducted at an elevated pressure of about 1 to about 250 bar.21 . The continuous process according to claim 20, wherein the elevated pressure is about 12 to about 120 bar.

22. The continuous process according to claim 1 , wherein the acetoacetate ester is a compound of formula 1whereinA is derived from an organic alcohol, x is at least 1 , y is 0 or at least 1 , and n is 0 or an integer of 1 to 10.

23. The continuous process according to claim 22, whereinA is derived from an organic monohydric alcohol, wherein the organic monohydric alcohol comprises a methanol, ethanol, 1 -propanol, 2-propanol, 1 -butanol, 2- butanol, 2-methylpropan-1-ol, 1 ,1 -dimethylethanol, 3-methylbutan-1-ol, 2- methylbutan-1-ol, 2,2-dimethylpropan-l-ol, pentan-3-ol, pen-tan-2-ol, 3- methylbutan-2-ol, 2-methylbutan-2-ol, hexan-1-ol, hexan-2-ol, hexan-3-ol, 2- methylpentan-1-ol, 3-methylpentan-1-ol, 4-methylpentan-1-ol, 2-methylpentan-2-ol, 3-methylpentan-2-ol, 4-methylpentan-2-ol, 2-methylpentan-3-ol, 3-methylpentan-3- ol, 2,2-dimethylbutan-1-ol, 2,3-dimethylbutan-1-ol, 3,3-dimethylbutan-1-ol, 2,3- dimethylbutan-2-ol, 3,3-dimethylbutan-2-ol, 2-ethylbutan-1-ol, 1 -heptanol, 2- heptanol, 3-heptanol, 4-heptanol, 1 -octanol, 2-octanol, nonal-1-ol, decan-1 -ol, undecan-1-ol, dodecan-1-ol, tridecan-1-ol, tetradecan-1-ol, pentadecan-1 -ol, hexadecan-1 -ol, octadecan-1 -ol, hexacosan-1-ol, triacontan-1-ol, (hydroxymethyl)acrylate, or a combination thereof, x is 1 , and y is 0.

24. The continuous process according to claim 22, whereinA is derived from an organic polyol, wherein the organic polyol includes a 1 ,4-butanediol, 1 ,6-hexanediol, neopentyl glycol, 4,8- bis(hydroxymethyl)tricyclo[5.2.1 . 02, 6]decane, 2-methyl-1 ,3 -propanediol, mono- di-, tri- and tetraethylene glycol, polyethylene glycol, mono-, di-, tri- and tetrapropylene glycol, polypropylene glycol, cyclohexane dimethanol, trimethylolethane, trimethylolpropane, ethoxylated trimethylolethane, propoxylated trimethylolethane, ethoxylated trimethylolpropane, propoxylated trimethylolpropane, pentaerythritol, glycerol, glycerol, or a combination thereof, and x + y is from 1 to the number of hydroxyl groups of the initial organic polyol A.

25. The continuous process according to claims 22, wherein the acetoacetate ester is a compound of formula 1-21-2 whereinA is derived from an organic alcohol, x is an integer of 1 to 6, preferably of 1 to 4, more preferably of 1 to 3, and in particular of 1 to 2 or 1 , and y is 0 or at least 1 , preferably 0 or an integer of 1 to 4, more preferably 0 or an integer of 1 to 3, and in particular 0 or an integer of 1 to 2.

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