PROCESS FOR MANUFACTURING HMB AND SALTS THEREOF
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to and the benefit of U.S. Provisional Patent
Application No. 61/555,423, filed on November 3, 201 1, U.S. Provisional Patent Application
No. 61/526,729, filed on August 24, 201 1, and U.S. Provisional Patent Application No.
61/523,531, filed on August 15, 201 1, the contents of which are incorporated by reference
herein.
TECHNICAL FIELD
[0002] The present disclosure relates to processes and systems for manufacturing betahydroxy-
beta-methylbutyrate or salts thereof, and more particularly, a continuous process and
system for manufacturing beta-hyrdoxy-beta-methylbutyrate or salts thereof, or both.
BACKGROUND
[0003] Conventional industrial processes for producing beta-hyrdoxy-beta-methylbutyrate
(HMB) are carried out in batch mode systems (i.e., a reaction is carried out in a first batch
reactor, and when the reaction is complete, the final product is transferred to a second batch
reactor to begin a new reaction). The conventional processes generally utilize sodium
hypochlorite (NaCIO) oxidation of diacetone alcohol (DIA) as the key synthetic reaction. In
general, the batch processes for HMB production provide a very poor yield, which in turn limits
the scale on which HMB can be produced.
SUMMARY
[0004] Provided herein are continuous processes and systems for manufacturing betahydroxy-
beta-methylbutyrate (HMB) or salts thereof, or both. The continuous processes and
systems provide a very good product yield, reduce cycle time, and allow for the large scale
production of HMB or salts thereof.
[0005] In a first embodiment, a continuous process for manufacturing beta-hydroxy-betametfiylbutyrate
or a salt thereof is provided. The process includes providing at least one oxidant
and diacetone alcohol at an equivalence ratio of the at least one oxidant to the diacetone alcohol
within a range of 3:1 to 4:1. The at least one oxidant and the diacetone alcohol are combined in
a flow reactor to form a product stream having a temperature of -10° C to 40° C. The product
stream comprises beta-hydroxy-beta-methylbutyrate or a salt thereof.
[0006] In a second embodiment, a continuous process for manufacturing calcium betahydroxy-
beta-methylbutyrate is provided. The continuous process includes combining at least
one oxidant with diacetone alcohol in a flow reactor to form a product stream having a
temperature of -10° C to 40° C. The equivalence ratio of the at least one oxidant to the diacetone
alcohol is within a range of 3:1 to 4:1. The product stream comprises a salt of beta-hydroxybeta-
methylbutyrate. The product stream is combined with at least one acid to form a second
product stream having a temperature of -5° C to 5° C. The second product stream comprises
beta-hydroxy-beta-methylbutyrate in free acid form. The second product stream is combined
with at least one organic solvent to create an organic solvent phase. The beta-hydroxy-betamethylbutyrate
in free acid form is preferentially soluble in the organic solvent phase. A
majority of the at least one organic solvent is removed from the organic solvent phase to produce
a concentrated organic solvent-product phase comprising beta-hydroxy-beta-methylbutyrate in
free acid form. The concentrated organic solvent-product phase comprising beta-hydroxy-betamethylbutyrate
is mixed with at least one source of calcium cations to form a third product
stream comprising calcium beta-hydroxy-beta-methylbutyrate. The third product stream has a
pH of at least 6. Calcium beta-hydroxy-beta-methylbutyrate is recovered from the third product
stream.
[0007] In a third embodiment, a system for manufacturing beta-hydroxy-beta-methylbutyrate
or a salt thereof is provided. The system includes a first pump in fluid communication with a
source of at least one oxidant and a first heat exchanger, and a second pump in fluid
communication with a source of diacetone alcohol and a second heat exchanger. In addition, the
system includes a flow reactor in fluid communication with the first heat exchanger and the
second heat exchanger. The at least one oxidant and the diacetone alcohol undergo an oxidation
reaction in the flow reactor to produce a product stream comprising beta-hydroxy-betamethylbutyrate
or a salt thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] Figure 1 illustrates a schematic of one embodiment of a continuous process for
manufacturing beta-hydroxy-beta-methylbutyrate or a salt thereof.
[0009] Figure 2 illustrates a schematic of one embodiment of a continuous process for
manufacturing calcium beta-hydroxy-beta-methylbutyrate.
DETAILED DESCRIPTION
[0010] Provided herein are continuous processes and systems for manufacturing betahydroxy-
beta-methylbutyrate (HMB) or salts thereof, or both. The continuous processes and
systems provide a very good yield, reduce cycle time, and allow for large scale production of
HMB or salts thereof. Moreover, the continuous processes and systems for manufacturing HMB
or salts thereof reduce energy consumption via increased cooling efficiency, reduce capital costs,
and provide more efficient process control when compared to conventional processes for
manufacturing HMB or salts thereof. The second embodiment is a sub-embodiment of the first
embodiment and the third embodiment provides a system which can be useful in practicing
certain processes according to the first and second embodiments.
[001 1] In a first embodiment, a continuous process for manufacturing beta-hydroxy-betamethylbutyrate
or a salt thereof is provided. The continuous process comprises providing at least
one oxidant and diacetone alcohol at an equivalence ratio of the at least one oxidant to the
diacetone alcohol within a range of 3:1 to 4:1; and combining the at least one oxidant and the
diacetone alcohol in a flow reactor to form a product stream having a temperature of -10° C to
40° C. The product stream comprises beta-hydroxy-beta-methylbutyrate or a salt thereof.
[0012] In a second embodiment, a continuous process for manufacturing calcium betahydroxy-
beta-methylbutyrate is provided. The continuous process according to the second
embodiment comprises combining at least one oxidant with diacetone alcohol in a flow reactor to
form a product stream having a temperature of -10° C to 40° C. The equivalence ratio of the at
least one oxidant to the diacetone alcohol is within a range of 3:1 to 4:1, and the product stream
comprises a salt of beta-hydroxy-beta-methylbutyrate. The product stream is combined with at
least one acid to form a second product stream having a temperature of -5° C to 5° C. The
second product stream comprises beta-hydroxy-beta-methylbutyrate in free acid form. The
second product stream is combined with at least one organic solvent to create an organic solvent
phase. The beta-hydroxy-beta-methylbutyrate in free acid form is preferentially soluble in the
organic solvent phase. A majority of the at least one organic solvent is removed from the
organic solvent phase to produce a concentrated organic solvent-product phase comprising betahydroxy-
beta-methylbutyrate in free acid form. The concentrated organic solvent-product phase
comprising beta-hydroxy-beta-methylbutyrate is mixed with at least one source of calcium
cations to form a third product stream comprising calcium beta-hydroxy-beta-methylbutyrate.
The third product stream has a pH of at least 6. Calcium beta-hydroxy-beta-methylbutyrate is
recovered from the third product stream.
[0013] In a third embodiment, a system for manufacturing beta-hydroxy-beta-methylbutyrate
or a salt thereof is provided. The system includes a first pump in fluid communication with a
source of at least one oxidant and a first heat exchanger, and a second pump in fluid
communication with a source of diacetone alcohol and a second heat exchanger. In addition, the
system includes a flow reactor in fluid communication with the first heat exchanger and the
second heat exchanger. The at least one oxidant and the diacetone alcohol undergo an oxidation
reaction in the flow reactor to produce a product stream comprising beta-hydroxy-betamethylbutyrate
or a salt thereof.
[0014] As discussed above with respect to the first, second, and third embodiments, at least
one oxidant and diacetone alcohol are combined in a flow reactor to form a product stream
comprising beta-hydroxy-beta-methylbutyrate or a salt thereof. The at least one oxidant and the
diacetone alcohol undergo an oxidation reaction in the flow reactor. One example of such an
oxidation reaction is illustrated in Scheme 1.
Scheme 1
[0015] As can be seen in Scheme 1, in certain embodiments, the at least one oxidant is
sodium hypochlorite, and the product of the oxidation reaction comprises sodium beta-hydroxybeta-
methylbutyrate. Although the example illustrated by Scheme 1 utilizes sodium hypochlorite
as the at least one oxidant, various materials may be utilized as the at least one oxidant. For
example, in certain embodiments according the first, second, and third embodiments, the at least
one oxidant is selected from the group consisting of sodium hypochlorite, calcium hypochlorite,
calcium hypobromite, calcium hypoiodite, sodium hypobromite, sodium hypoiodite, and
combinations thereof. When a calcium-based oxidant is utilized in the oxidation reaction, the
product of the oxidation reaction comprises calcium beta-hyrdoxy-beta-methylbutyrate.
[0016] In the first and second embodiments of the processes, the at least one oxidant and
diacetone alcohol are provided at an equivalence ratio of 3:1 to 4:1. As used herein, the term
"equivalence ratio" refers to the molar ratio of the at least one oxidant to diacetone alcohol. In
certain embodiments according to the first and second embodiments of the processes, the at least
one oxidant and the diacetone alcohol may be each provided neat, or alternatively dissolved or
dispersed in a solvent. For example, in certain embodiments of the first and second
embodiments of the processes, the at least one oxidant is provided as an aqueous solution and the
diacetone alcohol is neat. As used herein, the term "neat" refers to a pure or undiluted chemical
compound. In some embodiments, the at least one oxidant is an aqueous solution having a
concentration (by weight) of oxidant between 5% to 100%, including between 5% to 50%, also
including 8% to 35%, also including 10% to 16%, and further including 12% to 15%. In some
embodiments, the diacetone alcohol may have a concentration (by weight) from 80% to 100%,
also including 95% to 100%, and further including 99% to 100%.
[0017] The oxidation of the diacetone alcohol by the at least one oxidant is an exothermic
reaction that influences the product yield of beta-hydroxy-beta-methylbutyrate or a salt therof. A
higher reaction temperature degrades the product and produces unwanted byproducts, which may
include acetic acid or diols. Accordingly, in the first and second embodiments of the processes,
the oxidation reaction is carried out at a controlled temperature. For example, in the first and
second embodiments of the processes, the temperature of the product stream is within a range of
-10° C to 40° C. In certain embodiments according to the first and second embodiments, the
temperature of the product stream is within a range of -10° C to 0° C. In yet other embodiments
according to the first and second embodiments, the temperature of the product stream is around
-15 °C. By controlling the temperature of the product stream within the stated ranges, it has been
found that a higher product yield of beta-hydroxy-beta-methylbutyrate or a salt therof, when
compared to conventional processes, is achievable. As discussed in more detail below, in certain
embodiments according to the first and second embodiments, the temperature of the product
stream is controlled by reducing the temperature of the flow reactor, such as by jacketing or
otherwise cooling the flow reactor.
[0018] In order to provide optimal temperature control of the oxidation reaction, in certain
embodiments of the first and second embodiments, prior to or upon combining in the flow
reactor, the at least one oxidant is at a temperature of -20° C to 20° C, and the diacetone alcohol
is at a temperature of -20° C to 20° C. In certain other embodiments according to the first and
second embodiments, prior to or upon combining in the flow reactor, the at least one oxidant is at
a temperature of -20° C to 0° C, and the diacetone alcohol is at a temperature of -20° C to 0° C.
In order to achieve such temperature, in certain embodiments, the at least one oxidant and the
diacetone alcohol are cooled to a temperature of -20° C to 20° C prior to or upon being combined
in the flow reactor. The cooling of the at least one oxidant and the diacetone may be performed
utilizing virtually any type of cooling process sufficient to achieve the specified temperatures.
For example, and as shown in Figure 1, in certain embodiments according to the first and second
embodiments, the at least one oxidant and the diacetone alcohol may each flow through one or
more heat exchangers, such as a chiller, to achieve a temperature of -20° C to 20° C.
[0019] In certain embodiments according to the first and second embodiments, the at least one
oxidant and diacetone alcohol remain in the flow reactor for 3 minutes to 20 minutes to carry out
the oxidation reaction. In other words, the residence time of the oxidation reaction within the
flow reactor is 3 minutes to 20 minutes. As used herein, the term "residence time" refers to the
volume of the flow reactor divided by the volumetric flow rate (i.e., volumetric flow rate of the
at least one oxidant plus the volumetric flow rate of diacetone alcohol) entering the flow reactor.
In other embodiments, the at least one oxidant and diacetone alcohol remain in the flow reactor
for 4 minutes to 18 minutes, also including 8 minutes to 14 minutes, and further including 10
minutes to 12 minutes.
[0020] In certain embodiments according to the first embodiment of the continuous process
for manufacturing beta-hydroxy-beta-methylbutyrate or a salt thereof, the process further
comprises the step of collecting the product stream, which comprises a salt of beta-hydroxy-betamethylbutyrate.
For example, in certain embodiments, and as seen in Figure 1, the product
stream exiting the flow reactor may be collected in a vessel (120), such as a holding tank or a
batch reactor that may be used to further process the collected product stream comprising a salt
of beta-hydroxy-beta-methylbutyrate .
[0021] Referring now to Figure 2, in certain embodiments according to the first and second
embodiment, the continuous process may further comprise the step of combining the product
stream with at least one acid to form a second product stream having a temperature of -5° C to
5° C and a pH of less than 5. The second product stream comprises beta-hydroxy-betamethylbutyrate
in free acid form. In other words, the product stream comprising a salt of betahydroxy-
beta-methylbutyrate undergoes an acidification reaction at a temperature of -5° C to 5°
C and a pH of less than 5 to produce a second product stream comprising beta-hydroxy-betamethylbutyrate
in free acid form. In other embodiments according to the first and second
embodiments, the acidification reaction is carried out at a temperature of -5° C to 0° C and a pH
of less than 3. As seen in Figure 2, in certain embodiments, the product stream exiting the flow
reactor may be combined with at least one acid in a second flow reactor. Alternatively, in other
embodiments, a single flow reactor may be used and the at least one acid may be introduced into
the single flow reactor at a predetermined downstream location to combine with the product
stream. In addition, in yet other embodiments, the at least one acid may be combined with the
product stream collected in a vessel (120), as previously described with reference to Figure 1, to
carry out the acidification reaction to form beta-hydroxy-beta-methylbutyrate in free acid form.
[0022] Various types of acids may be utilized for the at least one acid. In certain
embodiments of the first and second embodiments, the at least one acid may be an aqueous acid
solution, a gas, or neat. For example, in certain embodiments according to the first and second
embodiments, the at least one acid is selected from the group consisting of hydrogen chloride
gas, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, bromic acid, and
combinations thereof. In certain embodiments according to the first and second embodiments,
the at least one acid combined with the product stream is a gaseous acid. For example, the
gaseous acid may be hydrogen chloride gas. Use of a gaseous acid, as opposed to an aqueous
acid solution, minimizes aqueous waste, as well as minimizes the amount of solvent required in
subsequent steps of the process.
[0023] In certain embodiments according to the first and second embodiments of the
continuous process, one or more reaction solvents may be used in connection with any of the
various reactions carried out in the process. The total amount of the reaction solvent utilized
(when reaction solvent is utilized) can be appropriately set under consideration of reactivity and
operability and is generally set within a wide range from 1 to 1000 parts by weight, from 5 to
500 parts by weight, from 5 to 50 parts by weight, and from 10 to 20 parts by weight, per 1 part
by weight of the substrate. In certain embodiments according to the first and second
embodiments, the reaction solvent is selected from the group consisting of water, ethanol, ethyl
acetate, and combinations thereof. For example, in certain embodiments of the first and second
embodiments, water is used as a reaction solvent in the oxidation reaction (with the at least one
oxidant as a substrate and the diacetone alcohol as a substrate) and the acidification reaction
(with a salt of beta-hydroxy-beta-methylbutyrate as a substrate and hydrogen chloride as a
substrate) disclosed herein. In addition, in certain embodiments according to the first and second
embodiments of the continuous process water is used as a reaction solvent in a neutralization
reaction (with beta-hydroxy-beta-methylbutyrate in free acid form as a substrate and at least one
source of calcium cations as a substrate) and a crystallization process (with a salt of betahydroxy-
beta-methylbutyrate as a substrate), as described below. Moreover, in certain
embodiments according to the first and second embodiments, water, ethanol, and ethyl acetate
are used as reaction solvents in the neutralization reaction. Furthermore, in other certain
embodiments according to the first and second embodiments, water and ethanol are used as
reaction solvents in the crystallization process.
[0024] Referring now to Scheme 2 (below), one embodiment of a synthetic process for
preparing calcium beta-hydroxy-beta-methylbutyrate is shown. In other embodiments, a similar
process may be followed, but other salts of beta-hydroxy-beta-methylbutyrate may be prepared
including, but not limited to, alkali metal salts, alkaline earth metal salts, or both. The first two
reactions seen in Scheme 2, are the oxidation of diacetone alcohol (1) with at least one oxidant
(here sodium hypochlorite (2)) to produce a salt of beta-hydroxy-beta-methylbutyrate (here the
sodium salt (3)), and the acidification of the salt of beta-hydroxy-beta-methylbutyrate with at
least one acid (here hydrochloric acid) to produce beta-hydroxy-beta-methylbutyrate in free acid
form (4). Scheme 2 further illustrates a neutralization step, or salt formation step, carried out by
treating the beta-hydroxy-beta-methylbutyrate in free acid form (4) with at least one source of
calcium cations (here calcium hydroxide) to form the calcium salt of beta-hydroxy-betamethylbutyrate
(5). Finally, Scheme 2 illustrates an optional step of recrystallizing the calcium
salt of beta-hydroxy-beta-methylbutyrate with, for example, a recrystallization solvent, such as
ethanol, to provide crystalline calcium beta-hydroxy-beta-methylbutyrate (6).
attofi
Scheme 2
[0025] As previously mentioned, in the continuous process according to the second
embodiment, and in certain embodiments of the continuous process according to the first
embodiment comprise combining at least one oxidant with diacetone alcohol in a flow reactor to
form a product stream and subsequently combining the product stream with at least one acid to
form a second product stream comprising beta-hydroxy-beta-methylbutyrate in free acid form.
Further, according to the continuous process of the second embodiment, and according to certain
embodiments of the first embodiment, the process comprises combining the second product
stream with at least one organic solvent to create an organic solvent phase. The beta-hydroxybeta-
methylbutyrate in free acid form is preferentially soluble in the at least one organic solvent
such that the beta-hydroxy-beta-methylbutyrate in free acid form enters the organic solvent
phase.
[0026] In certain embodiments according the first and second embodiments, the second
product stream and the at least one organic solvent may be combined in a continuous
countercurrent extractor such that the beta-hydroxy-beta-methylbutyrate in free acid form enters
the organic solvent phase. As mentioned above, the beta-hydroxy-beta-methylbutyrate in free
acid form is preferentially soluble in the at least one organic solvent. In certain embodiments
according the first and second embodiments, the at least one organic solvent is selected from the
group consisting of ethyl acetate, diethyl ether, and combinations thereof. One or more other
organic solvents may be utilized for the at least one organic solvent as long as the free acid form
of the beta-hydroxy-beta-methylbutyrate is preferentially soluble in such solvent(s).
[0027] In a further step of the continuous process of the second embodiment, and in certain
embodiments according to the first embodiment, a majority of the at least one organic solvent is
removed from the organic solvent phase to produce a concentrated organic solvent-product phase
comprising beta-hydroxy-beta-methylbutyrate in free acid form. Removal of a majority of the at
least one organic solvent from the organic solvent phase may be accomplished by a variety of
techniques. For example, in certain embodiments according to the first and second
embodiments, a majority of the at least one organic solvent is removed from the organic solvent
phase in an evaporator, such as a thin film or wiped film evaporator. In alternative
embodiments, a majority of the at least one organic solvent is removed from the organic solvent
phase via distillation. After a majority of the at least one organic solvent is removed from the
organic solvent phase, the concentrated organic solvent-product phase comprising beta-hydroxybeta-
methylbutyrate in free acid form may undergo further processing and the removed organic
solvent may be recovered or recycled to the process.
[0028] According to the continuous process of the second embodiment, and according to
certain embodiments of the first embodiment, the concentrated organic solvent-product phase
comprising beta-hydroxy-beta-methylbutyrate is mixed with at least one source of calcium
cations to form a third product stream comprising calcium beta-hydroxy-beta-methylbutyrate.
As previously noted with respect to Scheme 2, this mixing entails a neutralization, or salt
formation, producing the calcium salt of beta-hydroxy-beta-methylbutyrate. Preferably, the
mixing is carried out at a pH of at least 6 such that the third product stream comprising calcium
beta-hydroxy-beta-methylbutyrate has a pH of at least 6. In certain embodiments, the
neutralization, or salt formation, is carried out at a pH of at least 7 so that the third product
stream has a pH of at least 7.
[0029] In certain embodiments according to the first and second embodiments of the
continuous process, the at least one source of calcium cations comprises a calcium-based base,
and optionally comprises water as a solvent. In other embodiments according to the first and
second embodiments, the at least one source of calcium cations includes at least one calcium salt
and at least one base, and optionally comprises water as a solvent. In certain embodiments
according to the first and second embodiments, the at least one source of calcium cations is
selected from the group consisting of calcium hydroxide, calcium oxide, calcium carbonate,
calcium acetate, and combinations thereof.
[0030] In certain embodiments according to the first and second embodiments of the
continuous process, the mixing of the concentrated organic solvent-product phase comprising
beta-hydroxy-beta-methylbutyrate with at least one source of calcium cations to form a third
product stream comprising calcium beta-hydroxy-beta-methylbutyrate (or other salt form of betahydroxy-
beta-methylbutyrate) further includes simultaneously providing a recrystallization
solvent for mixing with the concentrated organic solvent-product phase and the at least one
source of calcium cations. In certain embodiments according to the first and second
embodiments of the continuous process, the recrystallization solvent is selected from the group
consisting of ethanol, ethyl acetate, acetone, water, and combinations thereof. Thus, in this
particular embodiment, the neutralization, or salt formation, is combined with recrystallization to
produce a solution comprising crystalline calcium beta-hydroxy-beta-methylbutyrate (or other
salt form of beta-hydroxy-beta-methylbutyrate). In certain embodiments according to the first
and second embodiments, to achieve the combined neutralization-recrystallization process, the
concentrated organic solvent-product phase comprising beta-hydroxy-beta-methylbutyrate, the at
least one source of calcium cations, and the recrystallization solvent are fed to a continuous
oscillatory baffled crystallizer, such as described by Lawton et al. "Continuous Crystallization of
Pharmaceuticals Using a Continuous Oscillatory Baffled Crystallizer," Organic Process
Research &Development, 2009, 13(6), pp 1357-1363, which is incorporated herein by reference
in its entirety, to produce a solution comprising crystalline calcium beta-hydroxy-betamethylbutyrate
(or other salt form of beta-hydroxy-beta-methylbutyrate).
[0031] According to the continuous process of the second embodiment, and according to
certain embodiments of the first embodiment, comprises recovering the calcium beta-hydroxybeta-
methylbutyrate (or other salt-form of the beta-hydroxy-beta-methylbutyrate) from the third
product stream. Recovering the calcium beta-hydroxy-beta-methylbutyrate (or other salt-form of
the beta-hydroxy-beta-methylbutyrate) may be carried out utilizing various techniques. For
example, in certain embodiments, the calcium beta-hydroxy-beta-methylbutyrate (or other saltform
of the beta-hydroxy-beta-methylbutyrate) is recovered from the third product stream by
continuous centrifugation. In the continuous centrifugation, the calcium beta-hydroxy-betamethylbutyrate
(or other salt-form of the beta-hydroxy-beta-methylbutyrate) is separated from
the solution {i.e., mother liquor), which solution may be further processed to recover any residual
calcium beta-hydroxy-beta-methylbutyrate (or other salt-form of the beta-hydroxy-betamethylbutyrate).
In addition, in certain other embodiments, the calcium beta-hydroxy-betamethylbutyrate
(or other salt-form of the beta-hydroxy-beta-methylbutyrate) is recovered from
the third product stream by filtration or decantation. Moreover, in certain embodiments, the
calcium beta-hydroxy-beta-methylbutyrate (or other salt-form of the beta-hydroxy-betamethylbutyrate)
is recovered from the third product stream by employing a spray drying
operation.
[0032] In certain embodiments of the continuous process according to the first and second
embodiments, the process further comprises removing residual solvent from the recovered
calcium beta-hydroxy-beta-methylbutyrate (or other salt-form of the beta-hydroxy-betamethylbutyrate).
The step of removing residual solvent from the recovered calcium betahydroxy-
beta-methylbutyrate (or other salt-form of the beta-hydroxy-beta-methylbutyrate) may
be performed by various methods. For example, in certain embodiments, the step of removing
residual solvent from the recovered calcium beta-hydroxy-beta-methylbutyrate (or other saltform
of the beta-hydroxy-beta-methylbutyrate) comprises drying the recovered calcium betahydroxy-
beta-methylbutyrate (or other salt-form of the beta-hydroxy-beta-methylbutyrate), such
as by feeding the recovered calcium beta-hydroxy-beta-methylbutyrate (or other salt-form of the
beta-hydroxy-beta-methylbutyrate) to a continuous dryer. It may not be possible to completely
remove all residual solvent, thus the solid calcium beta-hydroxy-beta-methylbutyrate (or solid
form of another salt-form of the beta-hydroxy-beta-methylbutyrate) may contain some amount of
residual solvent.
[0033] Referring now to Figure 1, a certain embodiment according to the third embodiment of
a system for manufacturing beta-hydroxy-beta-methylbutyrate or a salt thereof is illustrated.
(The third embodiment is not limited to the specific embodiment illustrated in Figure 1.) As can
be seen in Figure 1, the system comprises a first pump (102) in fluid communication with a
source of at least one oxidant (here aqueous sodium hypochlorite), and a first heat exchanger
(106). Also, as can be seen in Figure 1, the system includes a second pump (104) in fluid
communication with a source of diacetone alcohol, and a second heat exchanger (108). As
previously mentioned, the first and second heat exchangers (106, 108) are used to reduce the
temperature of the at least one oxidant and diacetone alcohol.
[0034] With continued reference to Figure 1, the illustrated and exemplary system according
to the third embodiment also includes a flow reactor ( 110) in fluid communication with the first
heat exchanger (106) and the second heat exchanger (108). As previously described herein, the
at least one oxidant and the diacetone alcohol are combined and undergo an oxidation reaction in
the flow reactor ( 110) to produce a product stream comprising beta-hydroxy-beta-methylbutyrate
or a salt thereof.
[0035] In certain embodiments according to the first, second and third embodiments of the
disclosure, the flow reactor comprises a tubular reactor having one or more static mixing
elements. Moreover, in certain other embodiments according to the first, second, and third
embodiments, the flow reactor includes a means of temperature control, such as an external or
internal cooling jacket or a cooling tank (refrigerant tank). By controlling the reaction
temperature (i.e., the temperature of the product stream) within the previously discussed ranges,
thermal degradation of the beta-hydroxy-beta-methylbutyrate or a salt thereof may be reduced or
even eliminated, thus increasing product yield. Suitable tubular reactors are commercially
available from, for example, Koflo Corporation, 309 Cary Point Drive, Cary, IL 60013. In
certain other embodiments, the flow reactor may comprise a single conduit or a plurality of
conduits through which the process streams flow in parallel. According to certain embodiments
of the first, second and third embodiments of the disclosure, the continuous production of betahydroxy-
beta-methylbutyrate or a salt thereof may be adjusted via a plurality of flow reactors
operating in parallel.
[0036] A wide variety of materials may be used for the flow reactor. For example, the
material for the flow reactor includes, but is not limited to, a stainless steel tube or a tube lined
with glass or TEFLON. In certain embodiments according to the first, second, and third
embodiments disclosed herein, the flow reactor is a tubular reactor having an inner diameter of
0.2 millimeters to 50 millimeters, also including 5 millimeters to 25 millimeters, and further
including 5 millimeters to 10 millimeters. Such an inner diameter provides sufficient area for
satisfactory heat transfer to better control the reaction temperature of the oxidation reaction,
acidification reaction, or both. With respect to the length of the flow reactor, it can be
determined based upon the amount of time the at least one oxidant and diacetone alcohol remain
in the flow reactor to carry out the oxidation reaction (i.e., the residence time required for the
reaction).
[0037] In certain embodiments according to the first, second, and third embodiments, the flow
reactor optionally includes an apparatus for accelerating the mixing of the at least one oxidant
and diacetone alcohol (hereinafter referred to as "premixer") in an inlet portion of the flow
reactor. Examples of the premixer include, but are not limited to, stirred mixers, ultrasonic
mixers, motionless mixers such as a static mixer, and piping joints.
[0038] A motionless mixer such as a static mixer can also be used as the flow reactor in
certain embodiments according to the first, second, and third embodiments disclosed herein.
Such a motionless mixer may provide better heat transfer characteristics, as well as a larger inner
diameter. Commercially available motionless mixers include, but are not specifically limited to,
a Sulzer static mixer and a Kenics static mixer. The motionless mixer may also have a premixer
in an inlet portion thereof. The number of elements in the static mixer is not specifically limited
but may be 10 or more, or 17 or more.
[0039] As previously mentioned with reference to Figure 1, in certain embodiments according
to the first, second, and third embodiments, the product stream exiting the flow reactor may be
collected in a vessel (120). The vessel (120) may be, for example, one or more holding tanks or
one or more batch reaction vessels used to further process the collected product stream
comprising a salt of beta-hydroxy-beta-methylbutyrate. For example, after collecting a
predetermined amount of the product stream in a first batch reaction vessel, the product stream
may be diverted to a second batch reactor for collection. The predetermined amount of the
product stream collected in the first batch reactor may then undergo an acidification reaction by
feeding to the batch reactor an amount of at least one acid to produce a second product stream
comprising beta-hydroxy-beta-methylbutyrate in free acid form.
[0040] With reference now to Figure 2, a certain embodiment of a system according to the
third embodiment is shown. As will be appreciated, several components of the illustrated system
shown in Figure 2 are similar to the components of the system shown in Figure 1. For example,
and as illustrated in Figure 2, the exemplary system comprises a first pump (202) in fluid
communication with a source of at least one oxidant (here aqueous sodium hypochlorite), and a
first heat exchanger (206). Also seen in Figure 2, the exemplary system includes a second pump
(204) in fluid communication with a source of diacetone alcohol, and a second heat exchanger
(208). The system according to the third embodiment the system according to the third
embodiment also includes a flow reactor (210) in f uid communication with the first heat
exchanger (206) and the second heat exchanger (208). As previously described herein, the at
least one oxidant and the diacetone alcohol are combined and undergo an oxidation reaction at
the specified conditions in the flow reactor (210) to produce a product stream comprising betahydroxy-
beta-methylbutyrate or a salt thereof.
[0041] With continued reference to Figure 2, certain embodiments of the system according to
the third embodiment comprise a third pump in fluid communication with a source of at least one
acid and the flow reactor. As previously described, the product stream comprising beta-hydroxybeta-
methylbutyrate or a salt thereof and the at least one acid are combined and undergo an
acidification reaction to produce a second product stream comprising beta-hydroxy-betamethylbutyrate
in free acid form. While the specific example shown in Figure 2 illustrates a
second flow reactor (220) in fluid communication with the flow reactor (210), the second flow
reactor (220) is optional, as the at least one acid may be combined with the product stream in the
flow reactor (210) at a predetermined downstream location.
[0042] In the continuous process reactions disclosed herein, in those embodiments where the
product stream and the at least one acid are combined and undergo the acidification reaction to
produce the second product stream, the second product stream may be further processed. For
example, in certain embodiments, a separation process is used to isolate the beta-hydroxy-betamethylbutyrate
in free acid form from the second product stream. To accomplish this isolation,
certain embodiments of the third embodiment of the disclosed system further includes a
continuous extractor in fluid communication with the flow reactor and a source of at least one
organic solvent. As seen in Figure 2, the second product stream is combined with at least one
organic solvent (here ethyl acetate) in the continuous extractor to create an organic solvent
phase. The at least one organic solvent is chosen such that the beta-hydroxy-beta-methylbutyrate
in free acid form is preferentially soluble in the at least one organic solvent as compared to the
second product stream. Thus, the organic solvent phase comprises beta-hydroxy-betamethylbutyrate
in free acid form and may be subjected to further processing, while a waste
stream exits the continuous extractor for treatment and disposal or recycling.
[0043] As seen in Figure 2, and in certain embodiments according to the third embodiment,
the organic solvent phase comprising beta-hydroxy-beta-methylbutyrate in free acid form may be
processed to recover the beta-hydroxy-beta-methylbutyrate in free acid form from the organic
solvent phase. For example, in certain embodiments according to the third embodiment, the
system comprises an evaporator in fluid communication with the continuous extractor such that
the beta-hydroxy-beta-methylbutyrate in free acid form is recovered from the organic solvent
phase. As briefly mentioned above, in certain embodiments the evaporator may be a thin film or
wiped film evaporator. However, in alternative embodiments, the system may comprise a
distillation column in fluid communication with the continuous extractor to recover betahydroxy-
beta-methylbutyrate in free acid form from the organic solvent phase.
[0044] Referring again to Figure 2, in those embodiments where the beta-hydroxy-betamethylbutyrate
in free acid form is recovered from the organic solvent phase, the beta-hydroxybeta-
methylbutyrate in free acid form may be subjected to further processing steps, such as a
purification step. Thus, in certain embodiments of the system according to the third
embodiment, the system further comprises a crystallizer in fluid communication with the
evaporator, a source of at least one separation solvent, and at least one source of calcium cations.
When the beta-hydroxy-beta-methylbutyrate in free acid form, the at least one recrstallization
solvent, and the at least one source of calcium cations are combined in the crystallizer, a third
product stream is produced comprising crystallized calcium beta-hydroxy-beta-methylbutyrate
(or other salt-form of the beta-hydroxy-beta-methylbutyrate). As mentioned above, in certain
embodiments according to the third embodiment of the system, the crystallizer comprises a
continuous oscillatory baffled crystallizer. However, other types of crystallizers and
crystallization systems may be utilized so long as they are capable of producing a third product
stream comprising crystallized calcium beta-hydroxy-beta-methylbutyrate (or other salt-form of
the beta-hydroxy-beta-methylbutyrate) .
[0045] With continued reference to Figure 2, in certain embodiments according to the third
embodiment, after crystallized calcium beta-hydroxy-beta-methylbutyrate (or other salt-form of
the beta-hydroxy-beta-methylbutyrate) is produced in the third product stream, the third product
stream may be further processed to recover the crystallized calcium beta-hydroxy-betamethylbutyrate.
To accomplish this separation, certain embodiments of the system according to
the third embodiment further comprise a continuous centrifugator in fluid communication with
the crystallizer. The continuous centrifugator separates the crystallized calcium beta-hydroxybeta-
methylbutyrate (or other salt-form of the beta-hydroxy-beta-methylbutyrate) from the
remaining components of the third product stream, which constitute the mother liquor. As
described above, the mother liquor may be further processed to recover any residual calcium
beta-hydroxy-beta-methylbutyrate (or other salt-form of the beta-hydroxy-beta-methylbutyrate).
In addition, in certain other embodiments, the system may comprise a filtration apparatus or a
decantation apparatus for recovering the crystallized calcium beta-hydroxy-beta-methylbutyrate
(or other salt-form of the beta-hydroxy-beta-methylbutyrate).
[0046] Optionally, the recovered crystallized calcium beta-hydroxy-beta-methylbutyrate (or
other salt-form of the beta-hydroxy-beta-methylbutyrate) may undergo a drying process to
remove residual solvent. Thus, in certain embodiments of the system according to the third
embodiment, the system comprises a continuous dryer in fluid communication with the
continuous centrifugator, as shown in Figure 2. The continuous dryer operates to remove
residual solvent the recovered crystallized calcium beta-hydroxy-beta-methylbutyrate (or other
salt-form of the beta-hydroxy-beta-methylbutyrate) to provide an even purer form of crystallized
calcium beta-hydroxy-beta-methylbutyrate (or other salt-form of the beta-hydroxy-betamethylbutyrate).
However, as briefly mentioned above, it may not be possible to completely
remove all residual solvent, thus the crystallized calcium beta-hydroxy-beta-methylbutyrate (or
other salt-form of the beta-hydroxy-beta-methylbutyrate) may still contain some amount of
residual solvent.
[0047] Although only the sodium salt and the calcium salt of beta-hydroxy-betamethylbutyrate
are explicitly discussed herein, the presently disclosed continuous processes and
systems may be utilized to produce other salt forms of beta-hydroxy-beta-methylbutyrate,
including alkali metal salts or alkaline earth metal salts or both. For example, the presently
disclosed continuous processes and systems may be used to produce a calcium salt, a sodium
salt, a potassium salt, a magnesium salt, a chromium salt, or combinations thereof.
[0048] The presently disclosed continuous processes and systems for manufacturing betahydroxy-
beta-methylbutyrate or a salt thereof will be better understood by reference to the
following examples, which are intended as an illustration of and not a limitation upon the scope
of the inventive concept.
EXAMPLES
[0049] The Examples provided below illustrate a comparison between different batch systems
and the presently disclosed continuous processes for manufacturing beta-hydroxy-betamethylbutyrate
or a salt thereof. Examples 1, 2 and 3 are comparative examples.
Example 1
[0050] Conventional batch mode preparation of beta-hydroxy-beta-methylbutyrate (HMB)
from diacetone alcohol (DIA), as disclosed in U.S. Patent No. 6,090,918, was reported to provide
an average yield of 0.26 pounds of HMB per pound of DIA (i.e., 25.6% yield), with the most
efficient batch achieving a yield of 0.325 pounds of HMB per pound of DIA (i.e., 32.0% yield).
The reaction was typically run in a reactor no greater than 200 gallons, with an average charge of
156 gallons of sodium hypochlorite and about 95 pounds of DIA, to produce about 25 pounds of
HMB per batch (i.e., 25.9% yield).
Example 2
[0051] Batch mode preparation of beta-hydro xy-beta-methylbutyrate (HMB) from diacetone
alcohol (DIA) employing the procedure and apparatus as disclosed in U.S. Patent No. 6,090,978,
which is fully incorporated herein by reference, was reported to provide an average yield of 0.44
pounds of HMB per pound of DIA (i.e., 43.3% yield). The highest batch yield with the
procedure of the '978 patent was reported to be 0.50 pounds of HMB per pound of DIA (i.e.,
49.2% yield). The oxidation of DIA was conducted at a reported temperature of 3° C-10° C for a
period of 30 minutes.
Example 3
[0052] Batch mode preparation of beta-hydroxy-beta-methylbutyrate (HMB) was conducted
in the laboratory to determine the batch mode yield at room temperature and reduced
temperature, as well as under bleach rich and bleach lean conditions. As used herein, the term
"bleach rich," refers to a HMB synthetic procedure wherein diacetone alcohol (DIA) is added
through controlled addition to a solution of oxidant, preferably sodium hypochlorite (NaCIO). As
used herein, the term "bleach lean," refers to a HMB synthetic procedure wherein oxidant,
preferably sodium hypochlorite, is added through controlled addition to DIA. In general,
reactions were conducted with a bleach to DIA equivalence ratio ranging from about 3:1 to about
4:1. Reaction yields were determined via HPLC analysis, and more specifically, according to
equation (1) wherein the concentration (moles/kg) of HMB in the reaction mixture (determined
by HPLC) was multiplied by the weight of the reaction mixture (weight of DIA + weight of
NaCIO solution) and divided by moles of DIA charged in the experiment.
HMB yield = [HMB] in reaction mixture * Weight of reaction mixture (1)
Moles of DIA charged
[0053] Under batch mode, room temperature, bleach rich operating conditions, 3 milliliters
(ml) of DIA was added through controlled addition to 50 ml of 11.9% aqueous sodium
hypochlorite solution, providing a 48%-50% yield of HMB as measured via HPLC analysis.
Batch mode, room temperature, bleach rich operating conditions were found to generally provide
a 48%-50% yield of HMB in about 12-20 minutes.
[0054] Under batch mode, room temperature, bleach lean operating conditions, 50 ml of
11.9% aqueous sodium hypochlorite solution was added through controlled addition to 3 ml of
DIA, providing a 10%-12% yield of HMB as measured via HPLC analysis. Room temperature,
bleach lean operating conditions were found to generally provide 10%-12% yield of HMB in
about 12-20 minutes.
[0055] Under batch mode, reduced temperature (3° C), bleach rich operating conditions, 3 ml
of DIA was added through controlled addition to 50 ml of 11.9% aqueous sodium hypochlorite
solution, providing a 60%-67% yield of HMB as measured via HPLC analysis. Batch mode,
reduced temperature, bleach rich operating conditions were found to generally provide a 60%-
67% yield of HMB in about 12-20 minutes.
[0056] Under batch mode, reduced temperature (3° C), bleach lean operating conditions, 50
ml of 11.9% aqueous sodium hypochlorite solution was added through controlled addition to 3
ml of DIA, providing a 16%-24% yield of HMB as measured via HPLC analysis. Batch mode,
reduced temperature, bleach lean operating conditions were found to generally provide a 16%-
24% yield of HMB in about 12-20 minutes.
[0057] The batch mode process production results confirm the exothermic nature of the
oxidation reaction of DIA, and that failure to control the temperature contributes to thermal
degradation of HMB. The results further indicate that at high pH, as is present in the bleach lean
conditions, DIA decomposition to acetone contributes to a low HMB yield as DIA reactant is
consumed by a side reaction with sodium hydroxide byproduct produced from the oxidation. As
will be discussed further below, the batch mode process also requires longer cycle times as
compared to continuous process conditions because slow addition of reactants is necessary in the
batch mode to maintain the desired reaction temperature and prevent thermal degradation of
HMB product, DIA decomposition to acetone, or both.
Example 4
[0058] Beta-hydroxy-beta-methylbutyrate (HMB) was prepared by a continuous process
according to the present disclosure. In particular, the sodium salt of HMB (NaHMB) was
prepared by a continuous flow process on a laboratory scale setup consistent with Figure 1, using
a tubular flow reactor purchased from Koflo Corporation, 309 Cary Point Drive, Cary, IL 60013.
The reaction temperature and residence time were varied to evaluate HMB yield as a function of
residence time and temperature. In general, reactions were conducted with a sodium
hypochlorite (NaClO) to diacetone alcohol (DIA) equivalence ratio ranging from about 3:1 to
about 4:1. The sodium hypochlorite used was an aqueous solution of 11.9% (by weight) sodium
hypochlorite. The diacetone alcohol utilized was neat. Reaction yields were determined via
HPLC analysis, and more specifically, according to equation (2) wherein the concentration
(moles/kg) of HMB in the reaction mixture (determined by HPLC) was multiplied by the
reaction flow rate (kg/hr) (determined by DIA flow rate + NaClO flow rate) and total reaction
collection time (hr), and then divided by moles of DIA, which was determined by multiplying
DIA flow rate (moles/hr) by total reaction collection time (hr).
HMB yield = [HMB] in rxn mixture * Rxn flow rate * Total rxn collection time (2)
DIA flow rate * Total rxn collection time
[0059] Flow process production of HMB at room temperature (~ 20° C) and a residence time
of 6.4 minutes generally provided an HMB yield of 46%-47%. Flow process production of
HMB at room temperature (~ 20° C) and a residence time of 12.8 minutes generally provided an
HMB yield of 46%-47%. Flow process production of HMB at reduced temperature (~ 3° C) and
a residence time of 3.2 minutes generally provided an HMB yield of about 52%. Flow process
production of HMB at reduced temperature (~ 3° C) and a residence time of 6.4 minutes
generally provided an HMB yield of about 58%-76%. Flow process production of HMB at
reduced temperature (3° C) and a residence time of 12.8 minutes provided an HMB yield of
64%-78%.
[0060] The flow process production of HMB results indicate that the smaller thermal mass
leads to better reaction control as compared to batch mode, which in turn leads to a higher yield
of HMB. Shorter residence times, as compared to batch mode, also contributes to higher HMB
yield because less NaHMB degradation or diacetone alcohol decomposition occurs. The flow
process also has additional advantages of better thermal efficiency, lower energy consumption,
and flexibility of scale-up as compared to the known batch mode processes. For example, the
continuous process of the present disclosure may be easily scaled-up or down via adjusting the
operating time of the process, or by adding or subtracting flow reactors.
[0061] Table 2, shown below, summarizes the results from Examples 1-4. The results
indicate that the continuous processes of the present disclosure provide the aforementioned
advantages over the known batch processes.
Table 2
BR = Bleach Rich; BL = Bleach Lean; RT = room temperature (~ 20° C); LT = low temperature (~ 3° C);
Min = Minutes; ND = not determined
[0062] To the extent that the term "includes" or "including" is used in the specification or the
claims, it is intended to be inclusive in a manner similar to the term "comprising" as that term is
interpreted when employed as a transitional word in a claim. Furthermore, to the extent that the
term "or" is employed (e.g., A or B) it is intended to mean "A or B or both." When the applicants
intend to indicate "only A or B but not both" then the term "only A or B but not both" will be
employed. Thus, use of the term "or" herein is the inclusive, and not the exclusive use. See
Bryan A. Garner, A Dictionary of Modern Legal Usage 624 (2d. Ed. 1995). Also, to the extent
that the terms "in" or "into" are used in the specification or the claims, it is intended to
additionally mean "on" or "onto." Furthermore, to the extent the term "connect" is used in the
specification or claims, it is intended to mean not only "directly connected to," but also
"indirectly connected to" such as connected through another component or components.
[0063] While the present application has been illustrated by the description of embodiments
thereof, and while the embodiments have been described in considerable detail, it is not the
intention of the applicants to restrict or in any way limit the scope of the appended claims to such
detail. Additional advantages and modifications will readily appear to those skilled in the art.
Therefore, the application, in its broader aspects, is not limited to the specific details, the
representative compositions and processes, and illustrative examples shown and described.
Accordingly, departures may be made from such details without departing from the spirit or
scope of the applicant's general inventive concept.
What is claimed is:
1. A continuous process for manufacturing beta-hydroxy-beta-methylbutyrate or a salt
thereof, comprising:
(A) providing at least one oxidant;
(B) providing diacetone alcohol, wherein an equivalence ratio of the at least one oxidant
to the diacetone alcohol is within a range of 3:1 to 4 :1; and
(C) combining the at least one oxidant with the diacetone alcohol in a flow reactor to
form a product stream, wherein the temperature of the product stream is within a range of -10° C
to 40° C.
2. The continuous process according to claim 1, wherein the temperature of the product
stream is within a range of -10° C to 0° C.
3. The continuous process according to claim 1 or 2, wherein the at least one oxidant is at a
temperature of -20° C to 20° C prior to or upon being combined with the diacetone alcohol, and
the diacetone alcohol is at a temperature of -20° C to 20° C prior to or upon being combined with
the at least one oxidant.
4. The continuous process according to any one of claims 1-3, wherein the at least one
oxidant is selected from the group consisting of sodium hypochlorite, calcium hypochlorite,
calcium hypobromite, calcium hypoiodite, sodium hypobromite, sodium hypoiodite, and
combinations thereof.
5. The continuous process according to any one of claims 1-4, wherein the at least one
oxidant and the diacetone alcohol remain in the flow reactor for 3 minutes to 20 minutes.
6. The continuous process according to any one of claims 1-5, further comprising collecting
the product stream, wherein the product stream comprises a salt of beta-hydroxy-betamethylbutyrate.
7. The continuous process according to any one of claims 1-5, further comprising
combining the product stream with at least one acid to form a second product stream having a
temperature of -5° C to 5° C and a pH of less than 5, wherein the second product stream
comprises beta-hydroxy-beta-methylbutyrate in free acid form.
8. The continuous process according to claim 7, wherein the at least one acid is selected
from the group consisting of hydrogen chloride gas, hydrochloric acid, hydrobromic acid,
hydroiodic acid, sulfuric acid, bromic acid, and combinations thereof.
9. The continuous process according to any one of claims 1-8, wherein the flow reactor
comprises a tubular reactor having one or more static mixing elements.
10. A continuous process for manufacturing calcium beta-hydroxy-beta-methylbutyrate,
comprising:
(A) combining at least one oxidant with diacetone alcohol in a flow reactor to form a
product stream having a temperature of -10° C to 40° C, wherein an equivalence ratio of the at
least one oxidant to the diacetone alcohol is within a range of 3:1 to 4:1, and the product stream
comprises a salt of beta-hydroxy-beta-methylbutyrate;
(B) combining the product stream with at least one acid to form a second product stream
having a temperature of -5° C to 5° C, wherein the second product stream comprises betahydroxy-
beta-methylbutyrate in free acid form;
(C) combining the second product stream with at least one organic solvent to create an
organic solvent phase, wherein the beta-hydroxy-beta-methylbutyrate in free acid form is
preferentially soluble in the organic solvent phase;
(D) removing a majority of the at least one organic solvent from the organic solvent
phase to produce a concentrated organic solvent-product phase comprising beta-hydroxy-betamethylbutyrate
in free acid form;
(E) mixing the concentrated organic solvent-product phase comprising beta-hydroxybeta-
methylbutyrate in free acid form with at least one source of calcium cations to form a third
product stream comprising calcium beta-hydroxy-beta-methylbutyrate, wherein the third product
stream has a pH of at least 6; and
(F) recovering the calcium beta-hydroxy-beta-methylbutyrate from the third product
stream.
11. The continuous process according to claim 10, wherein the temperature of the product
stream is within a range of -10° C to 0° C.
12. The continuous process according to claim 10 or 11, wherein the at least one oxidant is at
a temperature of -20° C to 20° C prior to or upon being combined with the diacetone alcohol, and
the diacetone alcohol is at a temperature of -20° C to 20° C prior to or upon being combined with
the at least one oxidant.
13. The continuous process according to any one of claims 10-12, wherein the at least one
oxidant is selected from the group consisting of sodium hypochlorite, calcium hypochlorite,
calcium hypobromite, calcium hypoiodite, sodium hypobromite, sodium hypoiodite, and
combinations thereof.
14. The continuous process according to any one of claims 10-13, wherein the at least one
acid is selected from the group consisting of hydrogen chloride gas, hydrochloric acid,
hydrobromic acid, hydroiodic acid, sulfuric acid, bromic acid, and combinations thereof.
15. The continuous process according to any one of claims 10-14, wherein the at least one
organic solvent is selected from the group consisting of ethyl acetate, diethyl ether, and
combinations thereof.
16. The continuous process according to any one of claims 10-15, wherein the at least one
source of calcium cations is selected from the group consisting of calcium hydroxide, calcium
oxide, calcium carbonate, calcium acetate, and combinations thereof.
17. The continuous process according to any one of claims 10-16, further including providing
a recrystallization solvent for mixing with the concentrated organic solvent-product phase and
the at least one source of calcium cations, wherein the recrystallization solvent is selected from
the group consisting of ethanol, ethyl acetate, acetone, water, and combinations thereof.
18. A system for manufacturing beta-hydroxy-beta-methylbutyrate or a salt thereof,
comprising:
(A) a first pump in fluid communication with (i) a source of at least one oxidant, and (ii)
a first heat exchanger;
(B) a second pump in fluid communication with (i) a source of diacetone alcohol, and
(ii) a second heat exchanger; and
(C) a flow reactor in fluid communication with the first heat exchanger and the second
heat exchanger;
whereby the at least one oxidant and the diacetone alcohol undergo an oxidation reaction
in the flow reactor to produce a product stream comprising beta-hydroxy-beta-methylbutyrate or
a salt thereof.
19. The system of claim 18, further comprising:
(A) a third pump in fluid communication with a source of at least one acid and the flow
reactor, wherein the product stream comprising beta-hydroxy-beta-methylbutyrate or a salt
thereof and the at least one acid undergo an acidification reaction to produce a second product
stream comprising beta-hydroxy-beta-methylbutyrate in free acid form;
(B) a continuous extractor in fluid communication with (i) the flow reactor, and (ii) a
source of at least one organic solvent, wherein the second product stream is combined with at
least one organic solvent in the continuous extractor to create an organic solvent phase, wherein
the beta-hydroxy-beta-methylbutyrate in free acid form is preferentially soluble in the at least
one organic solvent;
(C) an evaporator in fluid communication with the continuous extractor, wherein betahydroxy-
beta-methylbutyrate in free acid form is recovered from the organic solvent phase;
(D) a crystallizer in fluid communication with (i) the evaporator, (ii) a source of at least
one separation solvent, and (iii) at least one source of calcium cations, wherein the beta-hydroxybeta-
methylbutyrate in free acid form, the at least one recrstallization solvent, and the at least one
source of calcium cations are combined to produce a third product stream comprising
crystallized calcium beta-hydroxy-beta-methylbutyrate;
(E) a continuous centrifugator in fluid communication with the crystallizer, wherein the
crystallized calcium beta-hydroxy-beta-methylbutyrate is recovered from the third product
stream; and
(F) a continuous dryer in fluid communication with the continuous centrifugator,
wherein residual solvent is removed from the recovered crystallized calcium beta-hydroxy-betamethylbutyrate.